Chemical compounds

ABSTRACT

The invention relates to quinazoline derivatives of the formula:                    
     and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient. 
     The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

This is a continuation of application Ser. No. 09/203,764, filed Dec. 2,1998 which is a continuation of application Ser. No. 08/768,887 filesDec. 17, 1996 now U.S. Pat. No. 5,962,458.

The present invention relates to quinazoline derivatives, processes fortheir preparation, pharmaceutical compositions containing them as activeingredient, methods for the treatment of disease states associated withangiogenesis and/or increased vascular permeability and to their use inthe manufacture of medicaments for use in the production ofantiangiogenic and/or vascular permeability reducing effects inwarm-blooded animals such as humans.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman,1995, Nature Medicine 1: 27-31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139-155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841-844).

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signalling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefms-like tyrosine kinase receptor, Flt or Flt1, the kinase insertdomain-containing receptor, KDR (also referred to as Flk-1), and anotherfms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fltand KDR, have been shown to bind VEGF with high affinity (De Vries etal, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys.Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptorsexpressed in heterologous cells has been associated with changes in thetyrosine phosphorylation status of cellular proteins and calcium fluxes.

Compounds which have good activity against epidermal growth factor (EGF)receptor tyrosine kinase are disclosed in the European Patent No.0566226. The present invention is based on the discovery of compoundsthat surprisingly inhibit the effects of VEGF, a property of value inthe treatment of disease states associated with angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation.Compounds of the present invention possess higher potency against VEGFreceptor tyrosine kinase than against EGF receptor tyrosine kinase.Furthermore, compounds of the present invention, possess substantiallyhigher potency against VEGF receptor tyrosine kinase than against EGFreceptor tyrosine kinase or FGF R1 receptor tyrosine kinase. Thuscompounds of the invention which have been tested possess activityagainst VEGF receptor tyrosine kinase such that they may be used in anamount sufficient to inhibit VEGF receptor tyrosine kinase whilstdemonstrating no significant activity against EGF receptor tyrosinekinase or FGF R1 receptor tyrosine kinase.

According to one aspect of the present invention there is provided aquinazoline derivative of the formula I:

[wherein:

Y¹ represents —O—, —S—, —CH₂—, —SO—, —SO₂—, —NR⁵CO—, —CONR^(6—, —SO)₂NR⁷—, —NR⁸SO₂— or —NR⁹— (wherein R⁵, R⁶, R⁷, R⁸ and R⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);

R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl,cyano, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, or NR¹⁰R¹¹, (wherein R¹⁰and R¹¹, which may be the same or different, each represents hydrogen orC₁₋₃alkyl);

R² represents hydrogen, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino or nitro;

R⁴ is selected from one of the following eight groups:

1) X¹ (wherein X¹ represents a pyridone group, a phenyl group or a 5 or6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selectedfrom O, N and S, which pyridone, phenyl or heterocyclic group may carryup to 5 substituents selected from halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR¹²R¹³ and —NR¹⁴COR¹⁵ (whereinR¹², R¹³, R¹⁴, and R¹⁵, which may be the same or different, eachrepresents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));

2) C₁₋₅alkylX¹ (wherein X¹ is as defined hereinbefore);

3) C₂₋₅alkenylX¹ (wherein X¹ is as defined hereinbefore);

4) C₂₋₅alkynylX¹ (wherein X¹ is as defined hereinbefore);

5) C₁₋₅alkylY²X¹ (wherein Y² represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR¹⁶CO—, —CONR¹⁷—, —SO₂NR¹⁸—, —NR¹⁹—SO₂— or —NR²⁰— (wherein R¹⁶, R¹⁷,R¹⁸, R¹⁹ and R²⁰ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and X¹ is as defined hereinbefore);

6) C₂₋₅alkenylY³X¹ (wherein Y³ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or —NR²⁵— (wherein R²¹, R²²,R²³, R²⁴R²⁵ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and X¹ is as defined hereinbefore);

7) C₂₋₅alkynylY⁴X¹ (wherein Y⁴ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—N²⁶CO—, —CONR²⁷—, —SO₂NR²⁸—, —NR²⁹SO₂— or —NR³⁰— (wherein R²⁶, R²⁷,R²⁸, R²⁹ and R³⁰ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and X¹ is as defined hereinbefore); and

8) C₁₋₃alkylY⁵C₁₋₃alkylX¹ (wherein Y⁵ represents —O—, —S—, —SO—, —SO₂—,—NR³¹CO—, —CONR³²—, —SO₂NR³³—, —NR³⁴SO₂— or —NR³⁵— (wherein R³¹, R³²,R³³, R³⁴ and R³⁵ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and X¹ is as defined hereinbefore); Z represents—NH—, —O—, —S—, or —CH₂—; with the proviso that where R⁴ is selectedfrom one of the groups 1), 2), and 5) above and X¹ is unsubstitutedphenyl or substituted phenyl with 1 to 2 substituents selected fromhalogeno, C₁₋₄alkyl and C₁₋₄alkoxy, then m is an integer from 3 to 5and/or Z is —O—, —S—, or —CH₂—];

and salts thereof.

Advantageously Y¹ represents —O—, —S—, —CH₂—, —NR⁵CO—, —NR⁸SO₂— or —NR⁹—(wherein R⁵, R⁸ and R⁹ each independently represents hydrogen, C₁₋₂alkylor C₁₋₂alkoxyethyl).

Preferably Y¹ represents —O—, —S—, —CH₂—, —NR⁵CO—, —NR⁸SO₂— or —NH—(wherein R⁵ and R⁸ each independently represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

More preferably Y¹ represents —O—, —S—, —CH₂— or —NH—, especially —O—.

In another embodiment of the present invention Y¹ represents —O—,—NR⁵CO— or —NR⁸SO₂— (wherein R⁵ and R⁸ each independently representshydrogen or C₁₋₂alkyl).

In a further embodiment of the present invention Y¹ is —NHCO—.

In one embodiment of the invention R¹ represents hydrogen, hydroxy,C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, or NR¹⁰R¹¹ (wherein R¹⁰ and R¹¹are as defined hereinbefore). Conveniently however R¹ is hydrogen,hydroxy, cyano, nitro, trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy or amino.

R¹ is advantageously hydrogen, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy or amino.

R¹ is preferably hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy,more preferably hydrogen, hydroxy, methyl or methoxy, particularlyhydrogen, methyl or methoxy but especially methoxy.

In another embodiment of the present invention R¹ represents hydrogen,hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy orethoxy.

R² is advantageously hydrogen, halogeno, amino or nitro.

R² is preferably hydrogen, chloro or nitro, but especially hydrogen.

In one embodiment of the present invention R³ represents hydroxy.halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, trifluoromethyl, cyano, amino or nitro.

Advantageously in another embodiment of the present invention one R³substituent is meta-hydroxy and the other one or more are each selectedfrom halogeno and methyl.

In another embodiment of the invention the phenyl group bearing (R³)_(m)is of the formula IIa:

(wherein:

R^(a) represents hydrogen, methyl, fluoro or chloro;

R^(b) represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;

R^(c) represents hydrogen or hydroxy;

R^(d) represents hydrogen, fluoro or chloro, especially hydrogen orfluoro).

In a further embodiment of the invention the phenyl group bearing(R³)_(m) is preferably of the formula IIa wherein:

R^(a) represents hydrogen, fluoro or chloro;

R^(b) represents hydrogen, methyl, methoxy, bromo, fluoro or chloro,especially hydrogen, methyl or chloro;

R^(c) represents hydrogen or hydroxy; and

R^(d) represents hydrogen;

with the proviso that R^(a), R^(b) and R^(c) do not each representhydrogen.

Preferably the phenyl group bearing (R³)_(m) is the3-hydroxy-4-methylphenyl group, the 2-fluoro-5-hydroxy-4-methylphenylgroup, the 2-fluoro-4-bromophenyl, the 2-fluoro-4-chloro-5-hydroxyphenylor the 4-chloro-2-fluorophenyl group.

In a particular aspect of the present invention, the phenyl groupbearing (R³)_(m) is the 3-hydroxy-4-methylphenyl group, but especiallythe 2-fluoro-5-hydroxy-4-methylphenyl group. In a further embodiment ofthe present invention the phenyl group bearing (R³)_(m) is the4-chloro-2-fluorophenyl group.

Advantageously Y² represents —O—, —S—, —SO—, —SO₂—, —NR¹⁶CO—, —NR¹⁹SO₂—or —NR²⁰— (wherein R¹⁶, R¹⁹ and R²⁰ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably Y² represents, —O—, —S—, —SO—, —SO₂— or —NR²⁰— (wherein R²⁰represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably Y² represents —S—, —O— or —NR²⁰— (wherein R²⁰ representshydrogen or C₁₋₂alkyl), but most preferably is —O—, or —NR²⁰ (whereinR²⁰ is as hereinbefore defined).

Advantageously Y³ represents —O—, —S—, —SO₂—, —NR²¹CO—, —NR²⁴SO₂— or—NR²⁵— (wherein R²¹, R²⁴ and R²⁵ each independently represents hydrogen,C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably Y³ represents —O—, —S—, —SO—, —SO₂— or —NR²⁵— (wherein R²⁵represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably Y³ represents —O— or —NR²⁵— (wherein R²⁵ representshydrogen or C₁₋₂alkyl).

Advantageously Y⁴ represents —O—, —S—, —SO—, —SO₂—, —NR²⁶CO—, —NR²⁹SO₂—or —NR³⁰— (wherein R²⁶, R²⁹ and R³⁰ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably Y⁴ represents —O—, —S—, —SO—, —SO₂—or —NR³⁰— (wherein R³⁰represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably Y⁴ represents —O— or —NR³⁰— (wherein R³⁰ representshydrogen or C₁₋₂alkyl).

Advantageously Y⁵ represents —O—, —S—, —SO—, —SO₂— or —NR³⁵— (whereinR³⁵ represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably Y⁵ represents —O—, —S— or —NR³⁵— (wherein R³⁵ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

m is preferably 2 or 3.

Z may for example represent —NH— or —O—but Z is preferably —NH—.

X¹ preferably represents a pyridone group or a 5 or 6-membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which pyridone group or heterocyclic group may be substituted ashereinbefore defined.

Where X¹ is a 5 or 6-membered aromatic heterocyclic group, it preferablyhas 1 or 2 heteroatoms, selected from O, N and S, of which morepreferably one is N, and may be substituted as hereinbefore defined.

X¹ is particularly a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl,triazolyl or pyridazinyl group which group may be substituted ashereinbefore defined, more particularly a pyridone, pyridyl, imidazolyl,thiazolyl or triazolyl group, especially a pyridone, pyridyl, imidazolylor triazolyl group which group may be substituted as hereinbeforedefined.

Where R⁴ is C₁₋₅alkylX¹, C₂₋₅alkenylX¹, C₂₋₅alkynylX¹ orC₁₋₃alkylY⁵C₁₋₃alkylX¹, and X¹ is a nitrogen-containing 6-memberedaromatic heterocyclic group, said group is advantageously linked to thealkyl, alkenyl or alkynyl moiety via a carbon atom of X¹, said groupbeing such that a nitrogen atom is positioned para- to the carbon atomlinked to the alkyl, alkenyl or alkynyl moiety. The C₁₋₅alkyl moiety mayif desired be —(CH₂)_(n)—.

Where R⁴—Y¹ is X¹—(CH₂)_(n)—Y¹— and n is an integer from 0 to 5, Y¹ is—O—, —NH—, —S— or —CH₂— and X¹ is a nitrogen-containing 6-memberedaromatic heterocyclic group, said group is advantageously linked to—(CH₂)_(n)—Y¹— via a carbon atom of X¹, said group being such that anitrogen atom is positioned para- to the carbon atom linked to—(CH₂)_(n)—Y¹—.

In another example of interest, X¹ is pyrimidine which may besubstituted as hereinbefore defined.

In one embodiment of the invention X¹ represents a pyridone, phenyl or 5or 6-membered aromatic heterocyclic group with 1 to 3 heteroatomsselected from O, N and S, which group may preferably carry up to 2substituents, more preferably up to one substituent, selected from thegroup of substituents as hereinbefore defined.

In the definition of X¹, conveniently substituents are selected fromhalogeno, C₁₋₄alkyl, C₁₋₄alkoxy and cyano, more convenientlysubstituents are selected from chloro, fluoro, methyl and ethyl.

Conveniently R⁴ is selected from one of the following eight groups:

1) X¹ (wherein X¹ is as defined hereinbefore);

2) C₁₋₅alkylX¹ (wherein X¹ is as defined hereinbefore);

3) C₃₋₅alkenylX¹ (wherein X¹ is as defined hereinbefore);

4) C₃₋₅alkynylX¹ (wherein X is as defined hereinbefore);

5) C₁₋₅alkylY²X¹ (wherein Y² and X¹ are as defined hereinbefore);

6) C₃₋₅alkenylY³X¹ (wherein Y³ and X¹ are as defined hereinbefore);

7) C₃₋₅alkynylY⁴X¹ (wherein Y⁴ and X¹ are as defined hereinbefore); and

8) C₂₋₃alkylY⁵C₁₋₂alkylX¹ (wherein Y⁵ and X¹ are as definedhereinbefore).

Advantageously R⁴ is selected from one of the following eight groups:

1) X¹ (wherein X¹ is as defined hereinbefore);

2) C₁₋₅alkylX¹ (wherein X¹ is as defined hereinbefore); 3)1-X¹prop-1-en-3-yl, 1-X¹but-2-en-4-yl, 1-X¹but-1-en-3-yl,1-X¹pent-2-en-4-yl or 2-X¹pent-3-en-5-yl (wherein X¹ is as definedhereinbefore with the proviso that when R⁴ is 1-X¹prop-1-en-3-yl, X¹ islinked to the alkenyl group via a carbon atom);

4) 1-X¹prop-1-yn-3-yl, 1-X¹but-2-yn-4-yl, 1-X¹but-1-yn-3-yl,1-X¹pent-2-yn-4-yl or 2-X¹pent-3-yn-5-yl (wherein X¹ is as definedhereinbefore with the proviso that when R⁴ is 1-X¹prop-1-yn-3-yl, X¹ islinked to the alkynyl group via a carbon atom);

5) C₁₋₅alkylY²X¹ (wherein Y² and X¹ are as defined hereinbefore);

6) 1-(X¹Y³)prop-1-en-3-yl, 1-(X¹Y³)but-2-en-4-yl,1-(X¹Y³))but-1-en-3-yl, 1-(X¹Y³)pent-2-en-4-yl or 2-(X¹Y³)pent-3-en-5-yl(wherein Y³ and X¹ are as defined hereinbefore);

7)1-(X¹Y⁴)prop-1-yn-3-yl, 1-(X¹Y⁴)but-2-yn-4-yl, 1-X¹Y⁴)but-1-yn-3yl,1-(X¹Y⁴)pent-2-yn-4-yl or 2-(X¹Y⁴)pent-3-yn-5-yl (wherein Y⁴ and X¹ areas defined hereinbefore); and

8) C₂₋₃alkylY⁵C₁₋₂alkylX¹ (wherein Y⁵ and X¹ are as definedhereinbefore).

Preferably R⁴ is selected from one of the following eight groups:

1) X¹ (wherein X¹ is as defined hereinbefore);

2) C₁₋₅alkylX¹ (wherein X¹ is as defined hereinbefore);

3) 1-X¹but-2-en-4-yl (wherein X¹ is as defined hereinbefore);

4) 1-X¹but-2-yn-4-yl (wherein X¹ is as defined hereinbefore);

5) C₁₋₅alkylY²X¹ (wherein Y² and X¹ are as defined hereinbefore);

6) 1-(X¹Y³)but-2-en-4-yl (wherein Y³ and X¹ are as definedhereinbefore);

7) 1-(X¹Y⁴)but-2-yn-4-yl (wherein Y⁴ and X¹ are as definedhereinbefore); and

8) ethylY⁵methylX¹ (wherein Y⁵ and X¹ are as defined hereinbefore).

More preferably the compounds of formula (I) are of the formula (Ia):

(wherein R¹, R², R³, m, X¹, Y¹ and Z are as defined hereinbefore n is aninteger from 0 to 5 and y⁶ represents a direct bond, —O—, —S—, —SO—,—SO₂—, —NR³⁶CO—, —CONR³⁷—, —SO₂NR³⁸—, —NR³⁹SO₂— or —NR⁴⁰— (wherein R³⁶,R³⁷, R³⁸, R³⁹ and R⁴⁰ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl)).

Advantageously Y⁶ is a direct bond, —O—, —S—, —SO—, —SO₂— or —R⁴⁰—(wherein R⁴⁰ represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably Y⁶ is a direct bond, —O—, —S— or —NH—.

More preferably Y⁶ is a direct bond.

n is advantageously an integer from 0 to 3, preferably 1 to 3.

Therefore, for example, in a particular embodiment of the invention thecompounds of formula I are of the formula Ia wherein:

[Y¹ represents —O—, —NH—, —S— or —CH₂—;

n is an integer from 0 to 5;

X¹ represents a phenyl group or a 5 or 6-membered aromatic heterocyclicgroup with 1 to 3 heteroatoms selected from O, N and S, which phenyl orheterocyclic group may carry up to 5 substituents selected fromhalogeno, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy,carboxy, cyano, —CONR⁴¹R⁴² and —NR⁴³COR⁴⁴ (wherein R⁴¹, R⁴², R⁴³ andR⁴⁴, which may be the same or different, each represents hydrogen orC₁₋₄alkyl);

R¹ represents hydrogen, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio,or NR⁴⁵R⁴⁶ (wherein

R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen or C₁₋₃alkyl); R² represents hydrogen, hydroxy, halogeno,C₁₋₃alkyl, C₁₋₃alkoxy, trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino or nitro;

Z represents —NH— or —O—; and

Y⁶ is a direct bond;

with the proviso that where X¹ is unsubstituted phenyl or substitutedphenyl with 1 to 2 substituents selected from halogeno, C₁₋₄alkyl andC₁₋₄alkoxy, m is an integer from 3 to 5 or Z is —O—];

and salts thereof.

Preferred compounds of the present invention are:

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyridylmethoxy)quinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-(4-pyridyl)]amino)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]quinazoline

7-(4cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline

7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin4-yl)amino)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl-[1,2,4]-triazol-4-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-7-(2-(2,4-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-4-yl)ethoxy)quinazoline

4-(4-bromo-2-fluoroanilino)-7-(2-([1,2,4]-triazol-1-yl)ethoxy)-6-methoxyquinazoline

and salts thereof, especially hydrochloride salts thereof.

The following compounds of the present invention are especiallypreferred:

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinazoline

7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]quinazoline

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline

4-(4-chloro-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline

7-((2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline

4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline

7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4pyridyl)methoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4pyridyl)methoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline

7-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline

7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((1-methylimidazol-2-yl)methoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-7-((2-cyano4-pyridyl)methoxy)-6-methoxyquinazoline

and salts thereof, especially hydrochloride salts thereof, of which thefollowing are particularly preferred:

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]quinazoline

4-(4-chloro-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazoline

4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline

and salts thereof, especially hydrochloride salts thereof.

Another compound of interest is4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyrimidinylmethoxy)quinazolineand salts thereof especially hydrochloride salts thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘defined hereinbefore’ the saidgroup encompasses the first occurring and broadest definition as well aseach and all of the preferred definitions for that group.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Ananalogous convention applies to other generic terms. Unless otherwisestated the term “alkyl” advantageously refers to chains with 1-6 carbonatoms, preferably 1-4 carbon atoms. The term “alkoxy” as used herein,unless stated otherwise includes “alkyl” —O— groups in which “alkyl” isas hereinbefore defined. The term “aryl” as used herein unless statedotherwise includes reference to a C₆₋₁₀aryl group which may, if desired,carry one or more substituents selected from halogeno, alkyl, alkoxy,nitro, trifluoromethyl and cyano, (wherein alkyl and alkoxy are ashereinbefore defined). The term “aryloxy” as used herein unlessotherwise stated includes “aryl” —O-groups in which “aryl” is ashereinbefore defined. The term “sulphonyloxy” as used herein refers toalkylsulphonyloxy and arylsulphonyloxy groups in which “alkyl” and“aryl” are as hereinbefore defined. The term “alkanoyl” as used hereinunless otherwise stated includes alkylC═O groups in which “alkyl” is asdefined hereinbefore, for example ethanoyl refers to CH₃C═O. In thisspecification unless stated otherwise the term “alkenyl” includes bothstraight and branched chain alkenyl groups but references to individualalkenyl groups such as 2-butenyl are specific for the straight chainversion only. Unless otherwise stated the term “alkenyl” advantageouslyrefers to chains with 2-6 carbon atoms, preferably 4-5 carbon atoms. Inthis specification unless stated otherwise the term “alkynyl” includesboth straight and branched chain alkynyl groups but references toindividual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. Unless otherwise stated the term “alkynyl”advantageously refers to chains with 2-6 carbon atoms, preferably 4-5carbon atoms.

In formula I, as hereinbefore defined, hydrogen will be present atpositions 2 and 8 of the quinazoline group.

Within the present invention it is to be understood that a quinazolineof the formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits VEGF receptor tyrosine kinase activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.

It is also to be understood that certain quinazolines of the formula Iand salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which inhibit VEGFreceptor tyrosine kinase activity.

For the avoidance of any doubt, it is to be understood that when Y¹ is,for example, a group of formula —NR⁵CO—, it is the nitrogen atom bearingthe R⁵group which is attached to the quinazoline ring and the carbonyl(CO) group is attached to R⁴, whereas when Y¹ is, for example, a groupof formula —CONR⁶—, it is the carbonyl group which is attached to thequinazoline ring and the nitrogen atom bearing the R⁶ group is attachedto R⁴. A similar convention applies to the other two atom Y¹ groups suchas —NR⁸SO₂— and —SO₂NR⁷—. When Y¹ is —NR⁹— it is the nitrogen atombearing the R⁹ group which is linked to the quinazoline ring and to R⁴.An analogous convention applies to other groups. It is further to beunderstood that when Y¹ represents —NR⁹— and R⁹ is C₁₋₃alkoxyC₂₋₃alkylit is the C₂₋₃alkyl moiety which is linked to the nitrogen atom of Y¹and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁴ is, for example, a group of formulaC₁₋₅alkylY⁵C₁₋₅,alkylX¹, it is the terminal C₁₋₅alkyl moiety which isbound to Y¹, similarly when R⁴ is, for example, a group of formulaC₂₋₅alkenylX¹ it is the C₂₋₅alkenyl moiety which is bound to Y¹ and ananalogous convention applies to other groups. When R⁴ is a group1-X¹prop-1-en-3-yl it is the first carbon to which the group X¹ isattached and it is the third carbon which is linked to Y¹, similarlywhen R⁴ is a group 2-X¹pent-3-en-5-yl it is the second carbon to whichthe group X¹ is attached and it is the fifth carbon which is linked toY¹, and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when X¹carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety which isattached to X¹ whereas when X¹ carries a C₁₋₄alkylamino substituent itis the amino moiety which is attached to X¹ and an analogous conventionapplies to other groups.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic acids such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid as well as salts with organic acids affordingpharmaceutically acceptable anions, such as for example trifluoroacetic,citric or maleic acid. In addition where the compounds of formula I aresufficiently acidic, pharmaceutically acceptable salts may be formedwith an inorganic substance or organic base which affords apharmaceutically acceptable cation. Such salts include for example analkali metal salt, such as a sodium or potassium salt, an alkaline earthmetal salt such as a calcium or magnesium salt, an ammonium salt or forexample a salt with methylamine, dimethylamine, trimethylaimine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A compound of the formula I, or salt thereof, and other compounds of theinvention (as hereinafter defined) may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes include, for example, those illustrated in EuropeanPatent Applications Nos. 0520722, 0566226, 0602851 and 0635498. Suchprocesses, are provided as a further feature of the invention and are asdescribed hereinafter. Necessary starting materials may be obtained bystandard procedures of organic chemistry. The preparation of suchstarting materials is described within the accompanying non-limitingExamples. Alternatively necessary starting materials are obtainable byanalogous procedures to those illustrated which are within the ordinaryskill of an organic chemist.

Thus the following processes (a) to (g) and (i) to (v) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula III:

(wherein R¹, R², R⁴ and Y¹ are as defined hereinbefore and L¹ is adisplaceable group), with a compound of the formula IV:

wherein Z, R³ and m are as defined hereinbefore) whereby to obtaincompounds of the formula I and salts thereof. A convenient displaceablegroup L¹ is, for example, a halogeno, alkoxy (preferably C₁₋₄alkoxy),aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.

The reaction is advantageously effected in the presence of either anacid or a base. Such an acid is, for example, an anhydrous inorganicacid such as hydrogen chloride. Such a base is, for example, an organicamine base such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide. Alternatively such a base is, for example, analkali metal hydride, for example sodium hydride, or an alkali metal oralkaline earth metal amide, for example sodium amide or sodiumbis(trimethylsilyl)amide. The reaction is preferably effected in thepresence of an inert solvent or diluent, for example an alkanol or estersuch as methanol, ethanol, isopropanol or ethyl acetate, a halogenatedsolvent such as methylene chloride, trichloromethane or carbontetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulphoxide. The reaction is conveniently effected at atemperature in the range, for example, 10 to 150° C., preferably in therange 20 to 80° C.

The compound of the invention may be obtained from this process in theform of the free base or alternatively it may be obtained in the form ofa salt with the acid of the formula H—L¹ wherein L¹ has the meaningdefined hereinbefore. When it is desired to obtain the free base fromthe salt, the salt may be treated with a base as defined hereinbeforeusing a conventional procedure.

(b) Where the group of formula IIb:

(wherein R³ and m are as hereinbefore defined) represents a phenyl groupcarrying one or more hydroxy groups, a compound of the formula I andsalts thereof can be prepared by the deprotection of a compound offormula V:

(wherein ¹, m, R¹, R², R³, R⁴ and Z are as hereinbefore defined, Prepresents a phenolic hydroxy protecting group and p¹ is an integer from1 to 5 equal to the number of protected hydroxy groups and such thatm−p¹ is equal to the number of R³ substituents which are not protectedhydroxy). The choice of phenolic hydroxy protecting group P is withinthe standard knowledge of an organic chemist, for example those includedin standard texts such as “Protective Groups in Organic Synthesis” T. W.Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, including ethers (forexample, methyl, methoxymethyl, allyl and benzyl), silyl ethers (forexample, t-butyldiphenylsilyl and t-butyldimethylsilyl), esters (forexample, acetate and benzoate) and carbonates (for example, methyl andbenzyl). The removal of such a phenolic hydroxy protecting group may beeffected by any of the procedures known for such a transformation,including those reaction conditions indicated in standard texts such asthat indicated hereinbefore, or by a related procedure. The reactionconditions preferably being such that the hydroxy derivative is producedwithout unwanted reactions at other sites within the starting or productcompounds. For example, where the protecting group P is acetate, thetransformation may conveniently be effected by treatment of thequinazoline derivative with a base as defined hereinbefore and includingammonia, and its mono and di-alkylated derivatives, preferably in thepresence of a protic solvent or co-solvent such as water or an alcohol,for example methanol or ethanol. Such a reaction can be effected in thepresence of an additional inert solvent or diluent as definedhereinbefore and at a temperature in the range 0 to 50° C., convenientlyat or near 20° C.

(c) Production of those compounds of formula I and salts thereof whereinthe substituent Y¹ is —O—, —S— or —NR⁹— can be achieved by the reaction,conveniently in the presence of a base as defined hereinbefore, of acompound of the formula VI:

(wherein m, Y¹, R¹, R², R³ and Z are as hereinbefore defined) with acompound of formula VII:

R⁴—L¹  (VII)

(wherein R⁴ and L¹ are as hereinbefore defined); L¹ is a displaceablegroup for example a halogeno or sulphonyloxy group such as a bromo ormethanesulphonyloxy group. The reaction is preferably effected in thepresence of a base (as defined hereinbefore in process (a)) andadvantageously an inert solvent or diluent (as defined hereinbefore inprocess (a)), advantageously at a temperature in the range, for example10 to 150° C., conveniently at or near 50° C.

(d) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula VIII:

with a compound of the formula IX:

R⁴—Y¹—H  (IX)

(wherein L¹, R¹, R², R³, R⁴, Z, m and Y¹ are all as hereinbeforedefined). The reaction may conveniently be effected in the presence of abase (as defined hereinbefore in process (a)) and advantageously in aninert solvent or diluent (as defined hereinbefore in process (a)),advantageously at a temperature in the range, for example 10 to 150° C.,conveniently at or near 100° C.

(e) Compounds of the formula I and salts thereof wherein R⁴ isC₁₋₅alkylX², [wherein X² is selected from one of the following threegroups:

1) X¹ (wherein X¹ is as defined hereinbefore);

2) Y⁷X¹ (wherein Y⁷ represents —O—, —S—, —SO₂—, —NR⁴⁷CO—, —NR⁴⁸SO₂— or—NR⁴⁹— (wherein R⁴⁷, R⁴⁸ and R⁴⁹ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and X¹ is as defined hereinbefore);and

3) Y⁸C₁₋₅alkylY⁵X¹ (wherein Y⁸ represents —O—, —S—, —SO₂—, —NR⁵⁰CO—,—NR⁵¹SO₂— or —NR⁵²— (wherein R⁵⁰, R⁵¹ and R⁵² each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and Y⁵ and X¹ areas defined hereinbefore);]

may be prepared by reacting a compound of the formula X:

(wherein L¹, Y¹, R¹, R², R³, Z and m are as hereinbefore defined and R⁵³is C₁₋₅alkyl) with a compound of the formula XI:

X²—H  (XI)

(wherein X² is as defined hereinbefore) to give a compound of theformula I. The reaction may conveniently be effected in the presence ofa base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), and at a temperature in the range, for example 0 to 150°C., conveniently at about 50° C.

(f) The production of those compounds of the formula I and salts thereofwherein the substituent R¹ is represented by NR¹⁰R¹¹, where one or bothof R¹⁰ and R¹¹ are C₁₋₃alkyl, may be effected by the reaction ofcompounds of formula I wherein the substituent R¹ is an amino group andan alkylating agent, preferably in the presence of a base as definedhereinbefore. Such alkylating agents are C₁₋₃alkyl moieties bearing adisplaceable moiety as defined hereinbefore such as C₁₋₃alkyl halidesfor example C₁₋₃alkyl chloride, bromide or iodide. The reaction ispreferably effected in the presence of an inert solvent or diluent (asdefined hereinbefore in process (a)) and at a temperature in the range,for example, 10 to 100° C., conveniently at about ambient temperature.

(g) The production of compounds of formula I and salts thereof whereinone or more of the substituents R¹, R² or R³ is an amino group may beeffected by the reduction of a corresponding compound of formula Iwherein the substituent(s) at the corresponding position(s) of thequinazoline and/or phenyl ring is/are a nitro group(s). The reductionmay conveniently be effected as described in process (i) hereinafter.The production of a compound of formula I and salts thereof wherein thesubstituent(s) at the corresponding position(s) of the quinazolineand/or phenyl ring is/are a nitro group(s) may be effected by theprocesses described hereinbefore and hereinafter in processes (a-e) and(i-v) using a quinazoline compound selected from the compounds of theformulae (I-XXVII) in which the substituent(s) at the correspondingposition(s) of the quinazoline and/or phenyl ring is/are a nitrogroup(s).

Synthesis of Intermediates

(i) The compounds of formula III and salts thereof, constitute a furtherfeature of the present invention. Such compounds in which L¹ is halogenomay for example be prepared by halogenating a compound of the formulaXII:

(wherein R¹, R², R⁴ and Y¹ are as hereinbefore defined).

Convenient halogenating agents include inorganic acid halides, forexample thionyl chloride, phosphorus(III)chloride,phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenationreaction is conveniently effected in the presence of an inert solvent ordiluent such as for example a halogenated solvent such as methylenechloride, trichloromethane or carbon tetrachloride, or an aromatichydrocarbon solvent such as benzene or toluene. The reaction isconveniently effected at a temperature in the range, for example 10 to150° C., preferably in the range 40 to 100° C.

The compounds of formula XII and salts thereof which constitute afurther feature of the present invention may for example be prepared byreacting a compound of the formula XIII:

(wherein R¹, R² and L¹ are as hereinbefore defined) with a compound ofthe formula IX as hereinbefore defined. The reaction may conveniently beeffected in the presence of a base (as defined hereinbefore in process(a)) and advantageously in the presence of an inert solvent or diluent(as defined hereinbefore in process (a)), advantageously at atemperature in the range, for example 10 to 150° C., conveniently at ornear 100° C.

The compounds of formula XII and salts thereof may also be prepared bycyclising a compound of the formula XIV:

(wherein R¹, R², R⁴ and Y¹ are as hereinbefore defined, and A¹ is anhydroxy, alkoxy (preferably C₁₋₄alkoxy) or amino group) whereby to forma compound of formula XII or salt thereof. The cyclisation may beeffected by reacting a compound of the formula XIV, where A¹ is anhydroxy or alkoxy group, with formamide or an equivalent thereofeffective to cause cyclisation whereby a compound of formula XII or saltthereof is obtained, such as[3-(dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride. Thecyclisation is conveniently effected in the presence of formamide assolvent or in the presence of an inert solvent or diluent such as anether for example 1,4-dioxan. The cyclisation is conveniently effectedat an elevated temperature, preferably in the range 80 to 200° C. Thecompounds of formula XII may also be prepared by cyclising a compound ofthe formula XIV, where A¹ is an amino group, with formic acid or anequivalent thereof effective to cause cyclisation whereby a compound offormula XII or salt thereof is obtained. Equivalents of formic acideffective to cause cyclisation include for example atri-C₁₋₄alkoxymethane, for example triethoxymethane andtrimethoxymethane. The cyclisation is conveniently effected in thepresence of a catalytic amount of an anhydrous acid, such as a sulphonicacid for example p-toluenesulphonic acid, and an inert solvent ordiluent such as for example a halogenated solvent such as methylenechloride, trichloromethane or carbon tetrachloride, an ether such asdiethylether or tetrahydrofuran, or an aromatic hydrocarbon solvent suchas toluene. The cyclisation is conveniently effected at a temperature inthe range, for example 10 to 100° C., preferably in the range 20 to 50°C.

Compounds of formula XIV and salts thereof, which constitute a furtherfeature of the present invention, may for example be prepared by thereduction of the nitro group in a compound of the formula XV:

(wherein R¹, R², R⁴, Y¹ and A¹ are as hereinbefore defined) to yield acompound of formula XIV as hereinbefore defined. The reduction of thenitro group may conveniently be effected by any of the procedures knownfor such a transformation. The reduction of the nitro group mayconveniently be effected by any of the procedures known for such atransformation. The reduction may be carried out, for example, by thehydrogenation of a solution of the nitro compound in the presence of aninert solvent or diluent as defined hereinbefore in the presence of ametal catalyst such as palladium or platinum. A further reducing agentis, for example, an activated metal such as activated iron (produced forexample by washing iron powder with a dilute solution of an acid such ashydrochloric acid). Thus, for example, the reduction may be effected byheating a mixture of the nitro compound and the activated metal in thepresence of a solvent or diluent such as a mixture of water and alcohol,for example methanol or ethanol, to a temperature in the range, forexample 50 to 150° C., conveniently at or near 70° C.

Compounds of the formula XV and salts thereof which constitute a furtherfeature of the present invention, may for example be prepared by thereaction of a compound of the formula XVI:

(wherein R¹, R², L¹ and A¹ are as hereinbefore defined) with a compoundof the formula IX as hereinbefore defined to give a compound of theformula XV. The reaction of the compounds of formulae XVI and IX isconveniently effected under conditions as described for process (d)hereinbefore.

Compounds of formula XV and salts thereof, may for example also beprepared by the reaction of a compound of the formula XVII:

wherein R^(1 , R) ², Y¹ and A¹ are as hereinbefore defined with theproviso that Y¹ is not —CH₂—) with a compound of the formula VII ashereinbefore defined to yield a compound of formula XV as hereinbeforedefined. The reaction of the compounds of formulae XVII and VII isconveniently effected under conditions as described for process (c)hereinbefore.

The compounds of formula III and salts thereof may also be prepared forexample by reacting a compound of the formula XVIII:

(wherein R¹, R² and Y¹ are as hereinbefore defined with the proviso thatY¹ is not —CH₂— and L² represents a displaceable protecting group) witha compound of the formula VII as hereinbefore defined, whereby to obtaina compound of formula III in which L¹ is represented by L².

A compound of formula XVIII is conveniently used in which L² representsa phenoxy group which may if desired carry up to 5 substituents,preferably up to 2 substituents, selected from halogeno, nitro andcyano. The reaction may be conveniently effected under conditions asdescribed for process (c) hereinbefore.

The compounds of formula XVIII and salts thereof as hereinbefore definedmay for example be prepared by deprotecting a compound of the formulaXIX:

(wherein R¹, R², P, Y¹ and L² are as hereinbefore defined with theproviso that Y¹ is not CH₂). Deprotection may be effected by techniqueswell known in the literature, for example where P represents a benzylgroup deprotection may be effected by hydrogenolysis or by treatmentwith trifluoroacetic acid.

One compound of formula III may if desired be converted into anothercompound of formula III in which the moiety L¹ is different. Thus forexample a compound of formula III in which L¹ is other than halogeno,for example optionally substituted phenoxy, may be converted to acompound of formula III in which L¹ is halogeno by hydrolysis of acompound of formula III (in which L¹ is other than halogeno) to yield acompound of formula XII as hereinbefore defined, followed byintroduction of halide to the compound of formula XII, thus obtained ashereinbefore defined, to yield a compound of formula III in which L¹represents halogen.

(ii) The compounds of formula V and salts thereof, constitute a furtherfeature of the present invention, and may for example be prepared by thereaction of a compound of formula III as hereinbefore defined with acompound of the formula XX:

(wherein R³, m, p¹, P and Z are as hereinbefore defined). The reactionmay for example be effected as described for process (a) hereinbefore.

The compounds of formula V and salts thereof may also be prepared byreacting a compound of formula XXI:

(wherein R¹, R², L¹, Z, R³, m, p¹ and P are as hereinbefore defined)with a compound of formula IX as hereinbefore defined. The reaction mayfor example be effected as described for process (d) above.

The compounds of formula V and salts thereof may also be prepared byreacting a compound of formula XXII:

(wherein R¹, R², R³, Y¹, Z, P, p¹and m are as hereinbefore defined withthe proviso that Y¹ is not —CH₂—) with a compound of the formula VII ashereinbefore defined. The reaction may for example be effected asdescribed for process (c) hereinbefore.

The compounds of formula XXI and salts thereof may for example beprepared by reaction of a compound of formula XXIII:

(wherein R¹, R², and L¹ are as hereinbefore defined, and L¹ in the 4-and 7-positions may be the same or different) with a compound of theformula XX as hereinbefore defined. The reaction may be effected forexample by a process as described in (a) above.

Compounds of the formula XXII and salts thereof may be made by reactingcompounds of the formulae XIX and XX as hereinbefore defined, underconditions described in (a) hereinbefore, to give a compound of formulaXXIV:

(wherein R¹, R², R³, P, Z, Y¹, p¹ and m are as hereinbefore defined withthe proviso that Y¹ is not —CH₂—) and then deprotecting the compound offormula XXIV for example as described in (i) above.

(iii) Compounds of the formula VI and salts thereof, as hereinbeforedefined, may be made by deprotecting the compound of formula XXV:

(wherein R¹, R², R³, P, Z, Y¹ m are as hereinbefore defined) by aprocess for example as described in (i) above.

Compounds of the formula XXV and salts thereof may be made by reactingcompounds of the formulae XIX and IV as hereinbefore defined, under theconditions described in (a) hereinbefore, to give a compound of theformula XXV or salt thereof.

(iv) Compounds of the formula VIII and salts thereof as hereinbeforedefined may be made by reacting compounds of the formulae XXIII and IVas hereinbefore defined, the reaction may be effected by a process asdescribed in (a) above.

(v) Compounds of the formula X as defined hereinbefore and salts thereofmay for example be made by the reaction of a compound of formula VI asdefined hereinbefore with a compound of the formula XXVI:

L¹—R⁵³—L¹  (XXVI)

(wherein L¹ and R⁵³ are as hereinbefore defined) to give a compound ofthe formula X. The reaction may be effected for example by a process asdescribed in (c) above.

Compounds of the formula X and salts thereof may also be made forexample by deprotecting a compound of the formula XXVII:

(wherein L¹, R⁵³, Y, R¹, R², R³, P, m and p¹are as defined hereinbefore)by a process for example as described in (b) above.

Compounds of the formula XXVII and salts thereof may be made for exampleby reacting compounds of the formulae XXII and XXVI as definedhereinbefore, under the conditions described in (c) above.

When a pharmaceutically acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with, for example, an acid using a conventional procedure.

Many of the intermediates defined herein are novel, for example, thoseof the formulae III, V, XII, XIV and XV and these are provided as afurther feature of the invention.

Intermediates of the formulae VIII, X, XXI, XXII, XXIV, XXV and XXVIIare also provided as a further feature of the invention.

The identification of compounds which potently inhibit the tyrosinekinase activity associated with the VEGF receptors such as Flt and/orKDR and which inhibit angiogenesis and/or increased vascularpermeability is desirable and is the subject of the present invention.These properties may be assessed, for example, using one or more of theprocedures set out below:

(a) In Vitro Receptor Tyrosine Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit tyrosinekinase activity. DNA encoding VEGF or epidermal growth factor (EGF)receptor cytoplasmic domains may be obtained by total gene synthesis(Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or bycloning. These may then be expressed in a suitable expression system toobtain polypeptide with tyrosine kinase activity. For example VEGF andEGF receptor cytoplasmic domains, which were obtained by expression ofrecombinant protein in insect cells, were found to display intrinsictyrosine kinase activity. In the case of the VEGF receptor Flt (Genbankaccession number X51602), a 1.7 kb DNA fragment encoding most of thecytoplasmic domain, commencing with methionine 783 and including thetermination codon, described by Shibuya et al (Oncogene, 1990, 5:519-524), was isolated from cDNA and cloned into a baculovirustransplacement vector (for example pAcYM1 (see The BaculovirusExpression System: A Laboratory Guide, L. A. King and R. D. Possee,Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available fromInvitrogen Corporation)). This recombinant construct was co-transfectedinto insect cells (for example Spodoptera frugiperda 21(Sf21)) withviral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.(Details of the methods for the assembly of recombinant DNA moleculesand the preparation and use of recombinant baculovirus can be found instandard texts for example Sambrook et al, 1989, Molecular cloning—ALaboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press andO'Reilly et al, 1992, Baculovirus Expression Vectors—A LaboratoryManual, W.H. Freeman and Co, New York). For other tyrosine kinases foruse in assays, cytoplasmic fragments starting from methionine 806 (KDR,Genbank accession number L04947) and methionine 668 (EGF receptor,Genbank accession number X00588) may be cloned and expressed in asimilar manner.

For expression of cFlt tyrosine kinase activity, Sf1 cells were infectedwith plaque-pure cFlt recombinant virus at a multiplicity of infectionof 3 and harvested 48 hours later. Harvested cells were washed with icecold phosphate buffered saline solution (PBS) (10 mM sodium phosphatepH7.4, 138 mM NaCl, 2.7 mM KCl) then resuspended in ice cold HNTG/PMSF(20 mM Hepes pH7.5, 150 mM NaCl, 10% v/v glycerol, 1% v/v Triton X100,1.5 mM MgCl₂, 1 mM ethylene glycol-bis(βaminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonylfluoride); the PMSF is added just before use from a freshly-prepared 100mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. Thesuspension was centrifuged for 10 minutes at 13,000 rpm at 4° C., thesupernatant (enzyme stock) was removed and stored in aliquots at −70° C.Each new batch of stock enzyme was titrated in the assay by dilutionwith enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM Na₃VO₄, 0.1% v/v TritonX100, 0.2 mM dithiothreitol). For a typical batch, stock enzyme isdiluted 1 in 2000 with enzyme diluent and 50 μl of dilute enzyme is usedfor each assay well.

A stock of substrate solution was prepared from a random copolymercontaining tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (SigmaP3899), stored as 1 mg/ml stock in PBS at −20° C. and diluted 1 in 500with PBS for plate coating.

On the day before the assay 100 μl of diluted substrate solution wasdispensed into all wells of assay plates (Nunc maxisorp 96-wellimmunoplates) which were sealed and left overnight at 4° C.

On the day of the assay the substrate solution was discarded and theassay plate wells were washed once with PBST (PBS containing 0.05% v/vTween 20) and once with 50 mM Hepes pH7.4.

Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μlof diluted compound was transferred to wells in the washed assay plates.“Total” control wells contained 10% DMSO instead of compound. Twentyfive microliters of 40 mM MnCl₂ containing 8 μMadenosine-5′-triphosphate (ATP) was added to all test wells except“blank” control wells which contained MnCl₂ without ATP. To start thereactions 50 μl of freshly diluted enzyme was added to each well and theplates were incubated at room temperature for 20 minutes. The liquid wasthen discarded and the wells were washed twice with PBST. One hundredmicroliters of mouse IgG anti-phosphotyrosine antibody (UpstateBiotechnology Inc. product 05-321), diluted 1 in 6000 with PBSTcontaining 0.5% w/v bovine serum albumin (BSA), was added to each welland the plates were incubated for 1 hour at room temperature beforediscarding the liquid and washing the wells twice with PBST. One hundredmicroliters of horse radish peroxidase (HRP)-linked sheep anti-mouse Igantibody (Amersham product NXA 931), diluted 1 in 500 with PBSTcontaining 0.5% w/v BSA, was added and the plates were incubated for 1hour at room temperature before discarding the liquid and washing thewells twice with PBST. One hundred microliters of2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution,freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodiumperborate (made with 1 phosphate citrate buffer with sodium perborate(PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added toeach well. Plates were then incubated for 20-60 minutes at roomtemperature until the optical density value of the “total” controlwells, measured at 405 nm using a plate reading spectrophotometer, wasapproximately 1.0. “Blank” (no ATP) and “total” (no compound) controlvalues were used to determine the dilution range of test compound whichgave 50% inhibtion of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (HUVEC).

HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v foetal calfserum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/vFCS+3 μg/ml heparin+1 μg/ml hydrocortisone, at a concentration of 1000cells/well in 96 well plates. After a minimum of 4 hours they were dosedwith the appropriate growth factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml orb-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4days at 37° C. with 7.5% CO₂. On day 4 the cultures were pulsed with 1μCi/well of tritiated-thymidine (Amersham product TRA 61) and incubatedfor 4 hours. The cells were harvested using a 96-well plate harvester(Tomtek) and then assayed for incorporation of tritium with a Beta platecounter. Incorporation of radioactivity into cells, expressed as cpm,was used to measure inhibition of growth factor-stimulated cellproliferation by compounds.

(c) In Vivo Rat Uterine Oedema Assay

This test measures the capacity of compounds to reduce the acuteincrease in uterine weight in rats which occurs in the first 4-6 hoursfollowing oestrogen stimulation. This early increase in uterine weighthas long been known to be due to oedema caused by increased permeabilityof the uterine vasculature and recently Cullinan-Bove and Koos(Endocrinology, 1993,133:829-837) demonstrated a close temporalrelationship with increased expression of VEGF mRNA in the uterus. Wehave found that prior treatment of the rats with a neutralisingmonoclonal antibody to VEGF significantly reduces the acute increase inuterine weight, confirming that the increase in weight is substantiallymediated by VEGF.

Groups of 20 to 22-day old rats were treated with a single subcutaneousdose of oestradiol benzoate (2.5 μg/rat) in a solvent, or solvent only.The latter served as unstimulated controls. Test compounds were orallyadministered at various times prior to the administration of oestradiolbenzoate. Five hours after the administration of oestradiol benzoate therats were humanely sacrificed and their uteri were dissected, blottedand weighed. The increase in uterine weight in groups treated with testcompound and oestradiol benzoate and with oestradiol benzoate alone wascompared using a Student T test. Inhibition of the effect of oestradiolbenzoate was considered significant when p<0.05.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula 1,or a pharmaceutically acceptable salt thereof, as defined hereinbeforein association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintraveous, subcutaneous, intramuscular, intravascular or infusion) as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository. Ingeneral the above compositions may be prepared in a conventional mannerusing conventional excipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg. A unitdose in the range, for example. 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1-250 mg of active ingredient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

We have now found that compounds of the present invention inhibit VEGFreceptor tyrosine kinase activity and are therefore of interest fortheir antiangiogenic effects and/or their ability to cause a reductionin vascular permeability.

Thus according to this aspect of the invention there is provided the useof a compound of the formula I, or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for use in the production ofan antiangiogenic and/or vascular permeability reducing effect in awarm-blooded animal such as a human being.

According to a further feature of the invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal, such as a human being, in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The antiangiogenic and/or vascular permeability reducing treatmentdefined hereinbefore may be applied as a sole therapy or may involve, inaddition to a compound of the invention, one or more other substancesand/or treatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. In the field of medical oncology it isnormal practice to use a combination of different forms of treatment totreat each patient with cancer. In medical oncology the othercomponent(s) of such conjoint treatment in addition to theantiangiogenic and/or vascular permeability reducing treatment definedhereinbefore may be: surgery, radiotherapy or chemotherapy. Suchchemotherapy may cover three main categories of therapeutic agent:

(i) other antiangiogenic agents that work by different mechanisms fromthose defined hereinbefore (for example linomide, inhibitors of integrinαvβ3 function, angiostatin, razoxin, thalidomide);

(ii) cytostatic agents such as antioestrogens (for exampletamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens(for example megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrazole, vorazole, exemestane), antiprogestogens,antiandrogens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), LHRH agonists and antagonists (for examplegoserelin acetate, luprolide), inhibitors of testosterone5α-dihydroreductase (for example finasteride), anti-invasion agents (forexample metalloproteinase inhibitors like marimastat and inhibitors ofurokinase plasminogen activator receptor function) and inhibitors ofgrowth factor function, (such growth factors include for example EGF,FGFs, platelet derived growth factor and hepatocyte growth factor suchinhibitors include growth factor antibodies, growth factor receptorantibodies, tyrosine kinase inhibitors and serine/threonine kinaseinhibitors); and

(iii) antiproliferative/antineoplastic drugs and combinations thereof,as used in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); antitumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);antimitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan).

As stated above the compounds defined in the present invention are ofinterest for their antiangiogenic and/or vascular permeability reducingeffects. Such compounds of the invention are expected to be useful in awide range of disease states including cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation. Inparticular such compounds of the invention are expected to slowadvantageously the growth of primary and recurrent solid tumours of, forexample, the colon, breast, prostate, lungs and skin. More particularlysuch compounds of the invention are expected to inhibit the growth ofthose primary and recurrent solid tumours which are associated withVEGF, especially those tumours which are significantly dependent on VEGFfor their growth and spread, including for example, certain tumours ofthe colon, breast, prostate, lung, vulva and skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of testsystems for the evaluation of the effects of inhibitors of VEGF receptortyrosine kinase activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

[(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus, an oil-bath apparatus or aKoffler hot plate apparatus;

(vi) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet;

(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide

DMSO dimethylsulphoxide

NMP 1-methyl-2-pyrrolidinone

THF tetrahydrofuran

TFA trifluoroacetic acid.]

EXAMPLE 1

To a solution of4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline(93 mg, 0.2 mmol) in a mixture of methanol (6 ml) and methylene chloride(3 ml) was added at ambient temperature a 2M aqueous sodium hydroxidesolution (0.3 ml, 0.6 mmol). The mixture was stirred for 10 minutes atambient temperature, the solvents were partially evaporated, water wasadded to the residue and the solution was acidified with 0.1Mhydrochloric acid to pH6. The precipitate was filtered off, washed withwater and dried under vacuum to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazolinehydrochloride (67 mg, 87%). m.p. 249-251° C. ¹H NMR Spectrum: (DMSOd₆)2.13(s, 3H); 4.01(s, 3H); 5.40(s, 2H); 7.05(br s, 2H); 7.24(s, 1H);7.34(s, 1H); 7.51(d, 2H); 7.92(s, 1H); 8.44(s, 1H); 8.63(d, 2H); 9.34(s,1H); 9.47(br s, 1H) MS−ESI: 389 [MH]⁺

Elemental analysis: Found C 61.4 H 5.3 N 12.8 C₂₂H₂₀N₄O₃ 1.8 H₂O, 0.2HCl Requires C 61.7 H 5.6 N 13.1%

The starting material was prepared as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol),(J. Med. Chem. 1977, vol 20, 146-149), and Gold's reagent (7.4 g, 0.05mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours.Sodium acetate (3.0 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol)were added to the reaction mixture and it was heated for a further 3hours. The mixture was evaporated, water was added to the residue, thesolid was filtered off, washed with water and dried (MgSO₄).Recrystallisation from acetic acid gave7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g,0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred andheated at reflux for 1 hour. The mixture was evaporated, the residue wastaken up in toluene and evaporated to dryness to give7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45 g).

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(2.18 g, 6.47 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) andisopropanol (50 ml) was stirred and heated at reflux for 1 hour. Themixture was cooled to ambient temperature. The precipitate was filteredoff, washed with isopropanol and ether to give4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazolinehydrochloride (2.69 g, 89%).

A mixture of4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazolinehydrochloride (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst(0.27 g) in methanol (50 ml), DMF (12 ml ) and trichloromethane (50 ml)was stirred at ambient temperature under an atmosphere of hydrogen (1.5atmospheres) for 30 minutes. The catalyst was filtered off and thefiltrate evaporated. The residual solid was triturated in ether,filtered off and dried under vacuum at 50° C. to give4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (2.1 g, 100%).

To a solution of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (375 mg, 1 mmol) in DMF (16 ml ) were added at ambienttemperature potassium carbonate (415 mg, 3 mmol) and4-(bromomethyl)pyridine hydrobromide (J.Org.Chem. 1958, 23, 575, 278 mg,1.1 mmol). The reaction mixture was heated at 60° C. for 2 hours. Themixture was evaporated and the residue was partitioned between ethylacetate and water. The organic layer was washed with a saturated aqueoussodium chloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column flash chromatography, eluting with methylenechloride/methanol (95/5) to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline(93 mg, 22%). m.p. 201-202° C. ¹H NMR Spectrum: (DMSOd₆) 2.12(s, 3H);2.34(s, 3H); 4.02(s, 3H); 5.40(s, 2H); 7.27(s, 1H); 7.30(d, 1H); 7.51(d,2H); 7.62(s, 1H); 7.65(d, 1H); 7.91(s, 1H); 8.47(s, 1H); 8.63(d, 2H);9.53(s, 1H) MS−ESI: 453 [MNa]⁺, 431 [MH]⁺

Elemental analysis: Found C 65.4 H 5.5 N 12.7 C₂₄H₂₂N₄O₄ 0.6 H₂ORequires C 65.3 H 5.3 N 12.7%

3-Acetoxy-4-methylaniline used as a starting material was prepared asfollows:

To a mixture of 2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueoussodium hydroxide (24.5 ml) was added at ambient temperature aceticanhydride (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes,the solid was filtered off and the filtrate extracted with ethylacetate. The organic layers were combined, washed with an aqueoussaturated sodium chloride solution, dried (MgSO₄) and evaporated toyield 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this material(3.1 g, 15.9 mmol) and 10% palladium-on-charcoal catalyst (0.12 g) inethyl acetate (50 ml) was stirred at ambient temperature under anatmosphere of hydrogen for 2 hours. The catalyst was filtered off andthe filtrate evaporated to give 3-acetoxy-4-methylaniline (2.45 g, 94%).

EXAMPLE 2

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (750 mg) was reacted with 3-(bromomethyl)pyridinehydrobromide (Can. J. Chem. 1978, 56, 3068) (378 mg) to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-pyridylmethoxy)quinazoline(293 mg, 34%). m.p. 113-115° C. ¹H NMR Spectrum: (DMSOd₆) 2.09(s, 3H);2.30(s, 3H); 3.94(s, 3H); 5.32(s, 2H); 7.27(d, 1H); 7.32(s, 1H);7.43-7.46(m, 1H); 7.58(s, 1H); 7.59-7.63(m, 1H); 7.85(s, 1H);7.89-7.92(m, 1H); 8.45(s, 1H); 8.57(dd, 1H); 8.71(d, 1H); 9.48(s, 1H);MS−ESI: 453 [MNa]⁺, 431 [MH]⁺

Elemental analysis: Found C 64.4 H 5.7 N 11.7 C₂₄H₂₂N₄O₄ 0.85 H₂ORequires C 64.7 H 5.4 N 12.6%

EXAMPLE 3

The compound synthesised in Example 2 was further subjected to basiccleavage of the acetoxy protecting group using an analogous procedure tothat described in Example 1 to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyridylmethoxy)quinazoline(215 mg, 83%). m.p. 258-259° C. ¹H NMR Spectrum: (DMSOd₆) 2.12(s, 3H);3.94(s, 3H); 5.34(s, 2H); 7.05(s, 2H); 7.32(s, 1H); 7.35(s, 1H);7.46-7.49(m, 1H); 7.88(s, 1H); 7.93-7.95(m, 1H); 8.43(s, 1H); 8.60(dd,1H); 8.74(d, 1H); 9.33(s, 1H); 9.35(s, 1H) MS−ESI: 411 [MNa]⁺, 389 [MH]⁺

Elemental analysis: Found C 59.2 H 5.5 N 12.6 C₂₂H₂₀N₄O₃3 H₂O 0.07 HClRequires C 59.4 H 5.9 N 12.6%

EXAMPLE 4

4-(3-Acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline(170 mg, 0.39 mmol) was subjected to basic cleavage of the acetoxyprotecting group using an analogous procedure to that described inExample 1 to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazolinehydrochloride (58 mg, 38%). m.p. 236-238° C. ¹H NMR Spectrum: (DMSOd₆)2.30(s, 3H); 3.97(s, 3H); 5.34(s, 2H); 7.02(s, 2H); 7.23(s, 1H); 7.33(s,1H); 7.36-7.39(m, 1H); 7.56(d, 1H); 7.84-7.88(m, 1H); 7.87(s, 1H);8.39(s, 1H); 8.91(d, 1H); 9.32(s, 2H) MS−ESI: 389 [MH]⁺

Elemental analysis: Found C 55.8 H 5.5 N 11.8 C₂₂H₂₀N₄O₃ 3 H₂O 0.75 HClRequires C 56.2 H 5.7 N 11.9%

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (376 mg) was reacted with 2-(chloromethyl)pyridinehydrochloride (328 mg) to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline(170 mg, 40%). ¹H NMR Spectrum: (DMSOd₆) 2.12(s, 3H); 2.34(s, 3H);4.00(s, 3H); 5.37(s, 2H); 7.29(s, 1H); 7.31(s, 1H); 7.39 -7.42(m, 1H);7.58 -7.66(m, 3H); 7.87-7.90(m, 1H);7.91(s, 1H); 8.47(s, 1H); 8.64(d,1H); 9.52(s, 1H)

EXAMPLE 5

4-(3-Acetoxy-4-methylanilino)-6-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline(496 mg, 1.15 mmol) was subjected to basic cleavage of the acetoxyprotecting group using an analogous procedure to that described inExample 1 to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline(278 mg, 62%). m.p. 290-291° C. ¹H NMR Spectrum: (DMSOd₆) 2.13(s, 3H);4.02(s, 3H); 5.43(s, 2H); 7.05(s, 2H); 7.24(s, 1H); 7.35(s, 1H); 7.67(d,1H); 7.92(s, 1H); 8.41(s, 1H); 8.89(d, 1H); 9.24(s, 1H); 9.36(s, 1H);9.38(s, 1H) MS−ESI: 390 [MH]⁺

Elemental analysis: Found C 58.8 H 5.4 N 16.3 C₂₁H₁₉N₅O₃ 2.2 H₂ORequires C 58.8 H 5.5 N 16.3%

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (560 mg) was reacted in the presence of catalyticpotassium iodide with 4-(chloromethyl)pyrimidine (375 mg) to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline(496 mg, 74%). 1H NMR Spectrum: (DMSOd₆) 2.13(s, 3H); 2.35(s, 3H);4.03(s, 3H); 5.44(s, 2H); 7.27(s, 1H); 7.31(d, 1H); 7.62-7.68(m, 3H);7.93(s, 1H); 8.47(s, 1H); 8.89(d, 1H); 9.24(d, 1H); 9.54(s, 1H)

4-(Chloromethyl)pyrimidine was synthesised as follows:

A mixture of 4-methylpyrimidine (2 g, 21.2 mmol), N-chlorosuccinimide(4.26 g, 31.9 mmol) and dibenzoylperoxide (50 mg) in carbontetrachloride (100 ml) was heated at 80° C. for 2 hours. After cooling,the mixture was filtered and the filtrate was evaporated. The resultingoil was purified by flash chromatography using methylene chloride aseluant to give 4-(chloromethyl)pyrimidine as an orange oil (1 g, 37%).

EXAMPLE 6

A solution of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg, 1.06 mmol), (prepared as described for thestarting material in Example 1), 2-chloromethyl-1-methylimidazolehydrochloride (354 mg. 2.12 mmol), and potassium carbonate (585 mg) inDMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambienttemperature the reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried (MgSO₄) andevaporated. The residue was diluted with methanol (20 ml) and 2M sodiumhydroxide (I ml) was added. After stirring for 1 hour, the reactionmixture was diluted with water (20 ml) and 2M hydrochloric acid (3 ml)was added. The resulting solid was filtered off, washed with water anddried under vacuum to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazolinehydrochloride (150 mg, 29%). m.p. 257-260° C. ¹H NMR Spectrum: (DMSOd₆)2.17(s, 3H); 3.95(s, 3H); 4.03(s, 3H); 5.68(s, 2H); 7.02(dd, 1H);7.16(s, 2H); 7.64(s, 1H); 7.72(s, 1H); 7.80(s, 1H); 8.42(s, 1 H); 8.8(s,1H); 9.97(s, 1H); 11.38(s, 1H) MS−ESI: 392 [MH]⁺

Elemental analysis: Found C 51.7 H 5.5 N 14.2 C₂₁H₂₁N₅O₃ 1.65 H₂O 1.9HCl Requires C 51.4 H 5.4 N 14.3%

EXAMPLE 7

A solution of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg, 1.06 mmol), (prepared as described for thestarting material in Example 1), 4-chloromethyl-2-methylthiazolehydrochloride (390 mg, 2.12 mmol), potassium carbonate (438 mg) andpotassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 15hours. After cooling to ambient temperature the reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄) and evaporated. The residue was dilutedwith methanol (10 ml) and 2M sodium hydroxide (2 ml) was added. Afterstirring for 1 hour, the reaction mixture was diluted with water (20 ml)and 2M hydrochloric acid (3 ml) was added. The resulting solid wasfiltered off, washed with water and dried under vacuum to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinazoline hydrochloride (300 mg, 59%). m.p. 243-245° C. ¹H NMRSpectrum: (DMSOd₆) 2.17(s, 3H); 2.7(s, 3H); 4.0(s, 3H); 5.35(s, 2H);7.0(dd, 1H); 7.12(d, 1H); 7.16(d, 1H); 7.58(s, 1H); 7.75(s, 1H); 8.3(s,1H); 8.8(s, 1H); 9.5-9.8(br s, 1H); 11.3(s, 1H) MS−ESI: 409 [MH]⁺

Elemental analysis: Found C 51.9 H 5.0 N 11.6 S 6.8 C₂₁H₂₀N₄O₃S 1 H₂ORequires C 51.6 H 4.9 N 11.5 S 6.6% 1.7 HCl

EXAMPLE 8

To a solution of4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline(200 mg, 0.45 mmol) in methylene chloride/methanol (1/1) (20 ml) wasadded, a 2M aqueous sodium hydroxide solution (0.67 ml , 1.35 mmol). Themixture was stirred for 35 minutes at ambient temperature, the solventswere evaporated, water was added to the residue and the solution wasextracted with ethyl acetate. The organic layer was washed with water,brine, then dried (MgSO₄) and evaporated to give a white solid. Thissolid was then dissolved into a saturated solution of hydrochloric acidin methanol (10 ml) and stirred for 10 minutes. The solid product wasfiltered and dried under a vacuum, to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazolinehydrochloride (127 mg, 66%). m.p. 246-248° C. ¹H NMR Spectrum: (DMSOd₆)2.15(s, 3H); 3.98(s, 3H); 5.32(s, 2H); 6.98(dd, 1H); 7.10(s, 1H);7.14(d, 1H); 7.25(d, 1H); 7.40(s, 1H); 7.61(dd, 1H); 7.70(d, 1H);8.12(s, 1H); 8.74(s, 1 H); 9.60(s, 1H) MS−ESI: 394 [MH]⁺

Elemental analysis: Found C 58.3 H 4.8 N 9.4 S 7.3 Cl 7.5 C₂₁H₁₉N₃O₃S0.2 H₂O Re- C 58.4 H 4.8 N 9.7 S 7.4 Cl 7.8% 0.95 HCl quires

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg) was reacted in the presence of catalyticpotassium iodide with 3-chloromethylthiophene (Journal of the ChemicalSociety 1958, 4202) (168 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (210 mg, 46%). m.p. 201-203°C. ¹H NMR Spectrum: (DMSOd₆) 2.11 (s, 3H); 2.32(s, 3H); 3.95(s, 3H);5.27(s, 2H); 7.23(dd, 1H); 7.28(d, 1H); 7.32(s, 1H); 7.58-7.66(m, 4H);7.85(s, 1H); 8.46(s, 1H) 9.49(s, 1H) MS−ESI: 436 [MH]⁺

Elemental analysis: Found C 63.0 H 5.2 N 9.1 S 7.3 C₂₃H₂₁N₃O₄S 0.3 H₂ORequires C 62.7 H 5.0 N 9.5 S 7.3%

EXAMPLE 9

7-(2-Acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-6-methoxyquinazoline(220 mg, 0.44 mmol) was subjected to basic cleavage of the acetoxyprotecting group using an analogous procedure to that described inExample 8 to give,7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (41 mg, 19%). m.p. 202-204° C. ¹H NMR Spectrum: (DMSOd₆)2.16(s, 3H); 2.17(s, 3H); 4.01(s, 3H); 5.31(s, 2H); 6.98(dd, 1H);7.10(d, 1H); 7.17(d, 1H); 7.34(s, 1H); 7.47(s, 1H); 8.22(s, 1H); 8.80(s,1H); 9.68(br s, 1H) MS−ESI: 452 [MH]⁺

Elemental Found C 47.1 H 4.7 N 12.5 S 5.8 Cl 12.2 analysis: C₂₂H₂₁N₅O₄SRequires C 47.2 H 4.9 N 12.5 S 5.7 Cl 12.7% 2 H₂O 2 HCl

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg) was reacted in the presence of catalyticpotassium iodide with 2-acetamido-4-chloromethylthiazole (252 mg) togive7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-6-methoxyquinazoline(220 mg, 42%). ¹H NMR Spectrum: (DMSOd₆) 2.13(s, 3H); 2.15(s, 3H);2.35(s, 3H); 3.97(s, 3H); 5.24(s, 2H); 7.24-7.31(m, 2H); 7.37(s, 1H);7.63-7.66(m, 2H); 7.87(s, 1H); 8.48(s, 1H); 9.50(s, 1H) MS−ESI: 494[MH]⁺

EXAMPLE 10

4-(3-Acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline(342 mg, 0.76 mmol) was subjected to basic cleavage of the acetoxyprotecting group using an analogous procedure to that described inExample 8 to give4-(3-hydroxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazolinehydrochloride (209 mg, 62%). m.p. 252-254° C. ¹H NMR Spectrum: (DMSOd₆)2.20(s, 3H); 2.29(s, 3H); 2.52(s, 3H); 4.03(s, 3H); 5.23(s, 2H);7.03(dd, 1H); 7.15(d, 1H); 7.19(d, 1H); 7.44(s, 1H); 8.22(s, 1H);8.82(s, 1H); 9.67(s, 1H) MS−ESI: 407 [MH]⁺

Elemental analysis: Found C 59.1 H 5.4 N 12.6 Cl 8.0 C₂₂H₂₂N₄O₄ 0.25 H₂ORequires C 59.1 H 5.3 N 12.5 Cl 7.9% 1 HCl

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example1,4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg) was reacted in the presence of potassium iodide(16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give4-(3-acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline(342 mg, 72%). ¹H NMR Spectrum: (DMSOd₆) 2.18(s, 3H); 2.33(s, 3H);2.35(s, 3H); 2.46(s, 3H); 3.98(s, 3H); 4.98(s, 2H); 7.00(s, 1H); 7.15(s,1H); 7.22-7.25(m, 1H); 7.32(s, 1H); 7.43(dd, 1H); 7.51(s, 1H); 8.66(s,1H)

EXAMPLE 11

A solution of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (400 mg, 1.06 mmol), (prepared as described for thestarting material in Example 1), 4-(3-chloropropyl)pyridyl hydrochloride410 mg, 2.1 mmol), potassium carbonate (438 mg) and potassium iodide (40mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling toambient temperature the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried(MgSO₄) and evaporated. The residue was diluted with methanol (20 ml)and 2M sodium hydroxide (2 ml) was added. After stirring for 1 hour, thereaction mixture was diluted with water (20 ml) and concentratedhydrochloric acid (1 ml) was added. The resulting solid was filtered offand was purified by preparative C18 HPLC using a gradient ofmethanol/water (0% to 80%) as eluant. After evaporation of the methanol,concentrated hydrochloric acid (0.3 ml) was added and the solution wasevaporated to dryness. After trituration with acetone, the solid wasfiltered off and dried under vacuum to give4-(3-hydroxy4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazolinehydrochloride (305 mg, 59%). m.p. 278-282° C. ¹H NMR Spectrum: (DMSO-d₆)2.15(s, 3H); 2.3(m, 2H); 3.1(m, 2H); 3.96(s, 3H); 4.24(t, 2H); 6.98(dd,1H); 7.15(m,2H); 7.44(s, 1H); 7.96(d, 2H); 8.31(s, 1H); 8.77(s, 1H);8.81(d, 2H); 9.7(br s, 1H); 11.34(s, 1H) MS−ESI: 417 [MH]⁺

Elemental analysis: Found C 57.3 H 5.4 N 11.0 C₂₄H₂₄N₄O₃ 0.7 H₂O 1.95HCl Requires C 57.6 H 5.5 N 11.2%

The starting material was prepared as follows:

Thionyl chloride (1.6 ml) was added to a solution of 4-pyridine propanol(2 g, 14.5 mmol) in trichloromethane (20 ml) cooled at 0° C. Afterstirring for 1 hour at ambient temperature followed by 1 hour at 60° C.,the solvent was evaporated and the residue was triturated with ether togive 4-(3-chloropropyl)pyridyl hydrochloride as a white solid. ¹H NMRSpectrum: (DMSOd₆) 2.15(m, 2H); 3.02(t, 2H); 3.69(t, 2H); 7.96(d, 2H);8.84(d, 2H)

EXAMPLE 12

A solution of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (410 mg, 1.00 mmol), 4-(3-chloropropyl)pyridylhydrochloride (480 mg, 2.5 mmol), potassium carbonate (480 mg) andpotassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 15hours. After cooling to ambient temperature the reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄) and evaporated. The residue was dilutedwith methanol (10 ml) and 2M sodium hydroxide (2 ml) was added. Afterstirring for 1 hour, the reaction mixture was diluted with water (20 ml)and concentrated hydrochloric acid-(0.5 ml) was added. The resultingsolid was filtered off and was purified by preparative C18 HPLC using agradient of methanol/water (0% to 80%) as eluant. After evaporation ofthe methanol, concentrated hydrochloric acid (0.3 ml) was added and thesolution was evaporated to dryness. After trituration with acetone, thesolid was filtered off and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazolinehydrochloride (243 mg, 48%). m.p. 246-248° C. ¹H NMR Spectrum: (DMSOd₆)2.16(s, 3H); 2.30(m, 2H); 3.09(t, 2H); 3.95(s, 3H); 4.26(t, 2H); 6.90(d,1H); 7.11(d, 1H); 7.41(s, 1H); 7.94(d, 2H); 8.3(s, 1H); 8.77(s, 1H);8.80(d, 2H); 9.7(br s, 1H); 11.46(s, 1H) MS−ESI: 435 [MH]⁺

Elemental analysis: Found C 55.3 H 5.3 N 10.2 Cl 13.0 C₂₄H₂₃N₄O₃F 0.9H₂O Requires C 55.3 H 5.2 N 10.7 Cl 13.3% 1.95 HCl

The starting material was prepared as follows:

A solution of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (3 g,13 mmol), (prepared as described in EP 0307777 A2), in ethanol (60 ml)containing platinum(IV)oxide (300 mg) was stirred under hydrogen at 0.3atmosphere for 1 hour. After filtration and evaporation of the solvent,2-fluoro-5-methoxycarbonyloxy-4-methylaniline was isolated as a solid(2.6 g, 100%). ¹H NMR Spectrum: (CDCl₃) 2.07(s, 3H); 3.87(s, 3H);6.52(d, 1H); 6.80(d, 1H)

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(800 mg, 2.4 mmol), (prepared as described for the starting material inExample 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg,2.89 mmol) in isopropanol (20 ml) was refluxed for 2 hours. Aftercooling to ambient temperature, the solid was filtered, washed withisopropanol and dried under vacuum to give7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (1.0 g, 87%) ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.2(s,3H); 3.85(s, 3H); 4.0(s, 3H); 5.37(s, 2H); 7.3-7.55(m, 8H); 8.13(s, 1H);8.86(s, 1H) MS−ESI: 464 [MH]⁺

A solution of7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (700 mg, 1.45 mmol) in DMF (10 ml), methanol (10 ml) andtrichloromethane (10 ml) containing 10% palladium-on-charcoal (100 mg)was stirred under an atmosphere of hydrogen for 1 hour. After filtrationand evaporation of the solvent, the residue was triturated with ether,filtered and dried under vacuum to give4-(2-fluoro-5methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (570 mg, 98%). ¹H NMR Spectrum: (DMSOd₆) 2.23(s, 3H);3.87(s, 3H); 4.01(s, 3H); 7.37(s, 1H); 7.45(d, 1H); 7.5(d, 1H); 8.20(s,1H); 8.77(s, 1H); 11.35(s, 1H); 11.79(s, 1H) MS-ESI: 374 [MH]⁺

EXAMPLE 13

A stirred solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline(35mg, 0.1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (15 mg, 0.1mmol) in a mixture of ethereal hydrogen chloride (2 ml) and isopropanol(5 ml) was heated at reflux for 4 hours. The precipitated product wascollected by filtration, washed with acetone and dried under vacuum togive4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazolinehydrochloride (23mg, 47%). m.p. 257-260° C. ¹H NMR Spectrum: (DMSOd₆)2.15(s, 3H); 4.08(s, 3H); 5.60(s, 2H); 6.90(d, 1H); 7.07(d, 1H); 7.47(s,1H); 7.93(br d, 2H); 8.74(s, 1H); 8.89(br d, 2H); 9.62(br s, 1H);11.46(s, 1H) MS-ESI: 407 [MH]⁺

Elemental analysis: Found C 52.8 H 4.6 N 10.9 C₂₂H₁₉N₄O₃F 1 H₂O 2 HClRequires C 53.1 H 4.6 N 11.3%

The starting chloroquinazoline was prepared as follows:

Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol)was added to a solution of phenol (1.26 g, 13.3 mmol) in dryN-methylpyrrolidone (20 ml) and the mixture stirred for 10 minutes.7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7mmol), (prepared as described for the starting material in Example 1),was then added and the reaction mixture heated at 110° C. for 2 hours.The mixture was allowed to cool, water was added and the mixtureextracted with ethyl acetate (3×100 ml). The combined extracts were thenwashed with 2M sodium hydroxide solution, water and brine. Removal ofthe solvent under reduced pressure gave7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 95%) as a yellowishsolid. ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H); 5.37(s, 2H); 7.25-7.6(m,11H); 7.60(s, 1H); 8.54(s, 1H) MS-ESI: 359 [MH]⁺

7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (160 mg, 0.44 mmol) in TFA (3ml) was heated at reflux for 30 minutes. The solvent was removed byevaporation and the residue treated with aqueous sodium hydrogencarbonate solution. The precipitated product was collected byfiltration, washed with water and dried to give7-hydroxy-6-methoxy-4-phenoxyquinazoline (105 mg, 88%). ¹H NMR Spectrum:(DMSOd₆) 4.00(s, 3H); 7.20(s, 1H); 7.25-7.35(m, 3H); 7.4-7.55(m, 2H);7.58(s, 1H); 10.73(s, 1H) MS-ESI: 269 [MH]⁺

A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (95 mg, 0.35mmol), 4-chloromethyl pyridine hydrochloride (120 mg, 0.74 mmol) andpotassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) were heated at 80°C. for 2 hours. The reaction mixture was allowed to cool, water wasadded and the mixture extracted with ethyl acetate (3×50 ml). Thecombined extracts were then washed with water and dried (MgSO₄). Thesolvent was removed by evaporation and the residue trituated with anethyl acetate/hexane mixture to give6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (44 mg, 35%) as awhite solid. ¹H NMR Spectrum: (DMSOd₆) 4.02(s, 3H); 5.47(s, 2H);7.25-7.35(m, 3H); 7.45(s, 1H); 7.4-7.55(m, 4H); 7.62(s, 1H); 8.52(s,1H); 8.63(dd, 2H) MS-ESI: 360 [MH]⁺

A solution of 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (200mg, 0.56 mmol) in 2M hydrochloric acid (15 ml) was heated at reflux for90 minutes. The reaction mixture was allowed to cool and neutralised topH6-7 with aqueous ammonia. The precipitated product was extracted withmethanol/methylene chloride (1:9) and the extract solution dried(MgSO₄). Removal of the solvent by evaporation gave6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (90 mg, 57%)as a grey solid. ¹H NMR Spectrum: (DMSOd₆) 3.93(s, 3H); 5.35(s, 2H);7.18(s, 1H); 7.48(s, 1H); 7.50(m, 2H); 8.04(s, 1H); 8.62(m, 2H) MS-ESI:284 [MH]⁺

Phosphorus oxytrichloride (0.1 ml) was added to a mixture of6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (81 mg, 0.29mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml), and themixture heated at reflux for 1 hour. The volatiles were removed byevaporation and the residue partitioned between methylene chloride andaqueous ammonia. The organic extract was separated, dried (MgSO₄) andthe solvent removed by evaporation. The residue was purified bychromatography on silica eluting with ethyl acetate progressing throughincreasingly polar mixtures to methanol/methylene chloride (1/9) to give4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (40 mg, 41%). ¹H NMRSpectrum: (DMSOd₆) 4.04(s, 3H); 5.47(s, 2H); 7.46(s, 1H); 7.50(d, 2H);7.53(s, 1H); 8.60(d, 2H); 8.85(s, 1H) MS-ESI: 302 [MH]⁺

The starting aniline was prepared as described below:

Methyl chloroformate (6.8 ml, 88 mmol) was added over 30 minutes to asolution of 4-fluoro-2-methylphenol (10 g, 79 mmol) in 6% aqueous sodiumhydroxide solution at 0° C. The mixture was stirred for 2 hours, thenextracted with ethyl acetate (100 ml). The ethyl acetate extract waswashed with water (100 ml) and dried (MgSO₄) and the solvent removed byevaporation to give 4-fluoro-2-methylphenyl methyl carbonate (11.4 g,78%) as an oil. ¹H NMR Spectrum: (DMSOd₆) 2.14(s, 3H); 3.81(s, 3H);7.05(m, 1H); 7.1-7.25(m, 2H)

A mixture of concentrated nitric acid (6 ml) and concentrated sulphuricacid (6 ml) was added slowly to a solution of 4-fluoro-2-methylphenylmethyl carbonate (11.34 g, 62 mmol) in concentrated sulphuric acid (6ml) such that the temperature of the reaction mixture was kept below 50°C. The mixture was stirred for 2 hours, then ice/water was added and theprecipitated product collected by filtration. The crude product waspurified by chromatography on silica eluting with methylenechloride/hexane progressing through increasingly polar mixtures tomethanol/methylene chloride (1/19) to give4-fluoro-2-methyl-5-nitrophenol (2.5 g, 22%) as a solid. ¹H NMRSpectrum: (DMSOd₆; CD₃COOD) 2.31(s, 3H), 7.38(d, 1H) ,7.58(d, 1H)MS-ESI: 171 [MH]⁺

A mixture of 4-fluoro-2-methyl-5-nitrophenol (2.1 g, 13 mmol), ironpowder (1 g, 18 mmol) and iron(II)sulphate (1.5 g, 10 mmol) in water (40ml) was refluxed for 4 hours. The reaction mixture was allowed to cool,neutralised with 2M aqueous sodium hydroxide and extracted with ethylacetate (100 ml). The ethyl acetate extract was dried (MgSO₄) and thesolvent removed by evaporation to give2-fluoro-5-hydroxy-4-methylaniline (0.8 g, 47%) as a solid. ¹H NMRSpectrum: (DMSOd₆) 1.94(s, 3H); 4.67(s, 2H); 6.22(d, 1H); 6.65(d, 1H);8.68(s, 1H) MS-ESI: 142 []⁺

EXAMPLE 14

A solution of7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (259 mg, 0.54 mmol), (prepared as described for thestarting material in Example 12), in methanol (15 ml) containing 1Msodium hydroxide (1.6 ml) was stirred at ambient temperature for 1 hour.After addition of water (15 ml), concentrated hydrochloric acid (1 ml)was added and the mixture was stirred at ambient temperature for 15minutes. After evaporation of methanol, the precipitate was filtered,washed with water and dried under vacuum to give7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (192 mg, 80%). m.p. 294-298° C. ¹H NMR Spectrum: (DMSOd₆)2.2(s, 3H); 4.05(s, 3H); 5.35(s, 2H); 6.9(d, 1H); 7.12(d, 1H)7.35-7.5(m, 4H); 7.55-7.6(m, 2H); 8.25(s, 1H); 8.8(s, 1H); 9.7(s, 1H);11.35(s, 1H) MS-ESI: 406 [MH]⁺

Elemental analysis: Found C 62.3 H 4.9 N 9.3 C₂₃H₂₀N₃O₃F 0.16 H₂O 1 HClRequires C 62.1 H 4.8 N 9.5%

EXAMPLE 15

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(200 mg, 0.63 mmol), 2-(2-chloroethoxy)pyridine hydrochloride (120 mg,0.61 mmol) and potassium carbonate (260 mg, 1.9 mmol) in DMF (25 ml) washeated at 90° C. for 16 hours. The mixture was diluted with water andextracted with ethyl acetate. The extract was dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with ethyl acetate/methanol mixtures (100/0increasing to 90/10) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)quinazoline(20 mg, 7%) as an off-white solid. ¹H NMR Spectrum: (DMSOd₆) 3.99(s,3H); 4.35(t, 2H); 4.42(t, 2H); 6.22(t, 1H); 6.40(d, 1H); 7.42(s, 1H);7.55(d, 2H); 7.71(d, 1H); 7.85(t, 1H); 8.55(d, 1H); 9.62(s, 1H) MS-ESI:441 [MH]⁺

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(1.34 g, 4 mmol), (prepared as described for the starting material inExample 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in isopropanol(40 ml ) was refluxed for 1.5 hours. After cooling, the precipitate wascollected by filtration, washed with isopropanol then ether and driedunder vacuum to give7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (1.13 g, 64%). m.p. 239-242° C. ¹H NMR Spectrum: (DMSOd₆)4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H)MS-ESI: 410 [MH]⁺

Elemental analysis: Found C 59.2 H 4.3 N 9.4 C₂₂H₁₇N₃ClFO₂ 1 HClRequires C 59.2 H 4.1 N 9.41%

A solution of7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (892 mg, 2 mmol) in TFA (10 ml) was refluxed for 50minutes. After cooling, the mixture was poured onto ice. The precipitatewas collected by filtration, dissolved in methanol (10 ml) and basifiedto pH11 with aqueous ammonia. After concentration by evaporation, thesolid product was collected by filtration, washed with water then etherand dried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline as a yellowsolid (460 mg, 72%). m.p. 141-143° C. ¹H NMR Spectrum: (DMSOd₆) 3.95(s,3H); 7.05(s, 1H); 7.35(d, 1H); 7.54-7.59(m, 2H); 7.78(s, 1H); 8.29(s,1H) MS-ESI: 320-322 [MH]⁺

Thionyl chloride (0.55 ml, 7.55 mmol) was added to a solutionof,2-(2-hydroxyethoxy)pyridine (700 mg, 5.04 mmol), (J. Org. Chem. 1977,42, 1500), in trichloromethane (20 ml) at 5° C. The mixture was stirredfor 1 hour at 5° C., allowed to warm to ambient temperature and stirredfor a further 1 hour. The volatiles were removed by evaporation and byazeotroping with toluene to give 2-(2-chloroethoxy)pyridinehydrochloride (970 mg, 99%). ¹H NMR Spectrum: (DMSOd₆) 3.90(t, 2H);4.20(t, 2H); 6.22(d, 1H); 6.40(d, 1H); 7.44(dd, 1H); 7.64(d, 1H) MS-ESI:158 [MH]⁺

EXAMPLE 16

Triphenylphosphine (5.5 g, 21 mmol) followed by2-[N-methyl-N-(4-pyridyl)]aminoethanol (1.49 g, 9.8 mmol), (prepared asdescribed in EP 0359389 A1), were added to a stirred solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2.23 g, 7mmol), (prepared as described for the starting material in Example 15),in methylene chloride (60 ml) under nitrogen. Diethyl azodicarboxylate(3.65 g, 21 mmol) was then added dropwise and the mixture was stirred atambient temperature for 2 hours. Ethyl acetate (200 ml) was added andthe mixture was stirred for a further 2 hours. The solid product wascollected by filtration, washed with ethyl acetate, dried under vacuumand finally purified by column chromatography eluting with methylenechloride/methanol (75/25 followed by 60/40 and 50/50) to give a whitesolid. The purified product was dissolved in methylene chloride/methanoland the insolubles removed by filtration. Ethereal hydrogen chloride (10ml of 3M solution) was added to the filtrate and the volatiles wereremoved by evaporation. The residue was triturated with ether and thesolid product collected by filtration and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-[N-methyl-N-(4-pyridyl)]aminoethoxy)quinazolinehydrochloride (2.75 g, 75%) as a white solid. m.p. 222-227° C. ¹H NMRSpectrum: (DMSOd₆; CF₃COOD) 3.29(s, 3H); 3.95(s, 3H); 4.16(t, 2H);4.48(t, 2H); 7.05(br s, 1H); 7.37(s, 2H); 7.42(d, 1H); 7.58(t, 1H);7.65(dd, 1H); 8.18(s, 1H); 8.28(br s, 2H); 8.86(s, 1H) MS-ESI: 454 [MH]⁺

Elemental Analysis: Found C 51.2 H 4.8 N 12.9 C₂₃H₂₁N₅O₂ClF 0.9 H₂O 2HCl Requires C 50.9 H 4.6 N 12.9%

EXAMPLE 17

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(300 mg, 0.94 mmol), (prepared as described for the starting material inExample 15), 4-(2-chloroethoxy)pyridine hydrochloride (155 mg, 0.79mmol) and potassium carbonate (260 mg, 1.9 mmol) in NMP (20 ml) washeated at 90° C. for 2 hours, allowed to cool to ambient temperature andstirred for a further 18 hours. The mixture was diluted with water andextracted with ethyl acetate. The extract was washed with water, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography eluting with methylene chloride/methanolmixtures (100/0 increasing to 95/5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline(20 mg, 7%), m.p. 200-202° C. ¹H NMR Spectrum: (DMSOd₆) 3.90(s, 3H);4.50(s, 4H); 7.04(d, 2H); 7.26(s, 1H); 7.33(dd, 1H); 7.5-7.6(m, 2H);7.80(s, 1H); 8.35(s, 1H); 8.39(d, 2H); 9.52(s, 1H) MS-ESI: 441 [MH]⁺

The starting material was prepared as follows:

Thionyl chloride (0.75 ml, 10 mmol) was added to a solution of4-(2-hydroxyethoxy)pyridine (0.9 g, 6.5 mmol), (J. Chem. Soc. Perkin II,1987, 1867), in trichloromethane (20 ml) at 5° C. The mixture wasstirred for 1 hour at 5° C., allowed to warm to ambient temperature andstirred for a further 2 hours. The volatiles were removed by evaporationand by azeotroping with toluene to give 4-(2-chloroethoxy)pyridinehydrochloride (1.3 g, 100%). ¹H NMR Spectrum: (DMSOd₆) 4.03(t, 2H);4.62(t, 2H); 7.58(d, 2H); 8.77(d, 2H) MS-ESI: 158 [MH]⁺

EXAMPLE 18

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(300 mg, 0.94 mmol), (prepared as described for the starting material inExample 15), 1-(2-chloroethyl)-1,2-dihydro-2-pyridone (175 mg, 1.1mmol), (J. Am. Chem. Soc. 1951, 73, 3635), and potassium carbonate (260mg, 1.9 mmol) in DMF (30 ml) was heated at 80° C. for 3 hours, allowedto cool to ambient temperature and stirred for a further 18 hours. Themixture was diluted with water and extracted with ethyl acetate. Theextract was washed with water, dried (MgSO₄) and the solvent removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol/triethylamine mixtures (100/0/0increasing to 70/30/0.5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]quinazoline(50 mg, 12%). m.p. 209-211 ° C. ¹H NMR Spectrum: (DMSOd₆) 3.94(s, 3H);4.35(t, 2H); 4.41 (t, 2H); 6.22(dd, 1H); 6.40(d, 1H); 7.14(s, 1H);7.35(dd, 1H); 7.42(ddd, 1H); 7.5-7.6(m, 2H); 7.70(d, 1H); 7.80(s, 1H);8.35(s, 1H); 9.53(s, 1H) MS-ESI: 441 [MH]⁺

EXAMPLE 19

1-(3-Hydroxypropyl)-1,4-dihydro-4-pyridone (220 mg, 1.44 mmol) inmethylene chloride (4 ml) followed by 1,1′-(Azodicarbonyl)dipiperidine(720 mg, 2.86 mmol) were added to a stirred solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg,0.94 mmol), (prepared as described for the starting material in Example15), and tributylphosphine (0.69 ml, 2.8 mmol) in methylene chloride (20ml) under nitrogen at 5° C. The mixture was stirred at 5° C. for 3hours, allowed to warm to ambient temperature and stirred for a further18 hours. The solvent was removed by evaporation and the residuepartitioned between ethyl acetate and water. The organic phase wasseparated, dried (MgSO₄), and solvent removed by evaporation. Theresidue was purified by column chromatography eluting with methylenechloride/methanol/triethylamine mixtures (100/0/0 increasing to70/30/0.5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[3-(4-oxo-1,4-dihydro-1-pyridyl)propoxy]quinazoline(48 mg, 11%). m.p. >250° C. ¹H NMR Spectrum: (DMSOd₆) 3.56(m, 2H);4.00(s, 3H); 3.54(t, 2H); 4.38(t, 2H); 7.42(d, 1H); 7.5-7.65(m, 5H);8.43(s, 1H); 8.65-8.75(m, 4H) MS-ESI: 455 [MH]⁺

The starting material was prepared as follows:

Sodium hydride (946 mg of a 50% suspension in mineral oil, 19.7 mmol)was added to a solution of 4-hydroxypyridine (1.88 g, 19.7 mmol) in DMF(50 ml) and the mixture stirred for 30 minutes.2-(3-Bromopropoxy)tetrahydropyran (4.0 g, 17.9 mmol), (J. Chem. Soc.1963, 3440), was added and the mixture heated at 100° C. for 3 hours.The reaction mixture was allowed to cool, diluted with water andextracted with ethyl acetate. The extract was washed with water, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography eluting with methylene chloride/methanolmixtures (100/0 increasing to 95/5) to give1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (1.5 g,35%). ¹H NMR Spectrum: (DMSOd₆) 1.35-1.75(m, 6H); 1.95(t, 2H);3.35-3.5(m, 2H); 3.65-3.8(m, 2H); 4.12(t, 2H); 4.57(s, 1H); 6.95(s, 2H);7.94(s, 2H).

A solution of1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (0.75 g,3.16 mmol) in acetic acid (8 ml), THF (4 ml) and water (4 ml) was heatedat 50° C. for 4 hours. The volatiles were removed by evaporation to give1-(3-hydroxypropyl)-1,4-dihydro-4-pyridone (480 mg, 99%) as an off-whitesolid. ¹H NMR Spectrum: (DMSOd₆) 1.9-1.95(m, 2H); 1.97-2.05(m, 2H);4.0-4.1(m, 2H); 6.91(m, 2H); 8.36(m, 2H) MS-ESI: 154 [MH]⁺

EXAMPLE 20

1-(2-Hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 1.6 mmol) was addedto a stirred solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (230 mg, 0.7mmol), (prepared as described for the starting material in Example 15),and tributylphosphine (0.53 ml, 2.1 mmol) in methylene chloride (20 ml)under nitrogen at 5° C. 1,1′-(Azodicarbonyl)dipiperidine (552 mg, 2.2mmol) was added in portions over 10 minutes and the mixture was stirredat 5° C. for 2 hours, allowed to warm to ambient temperature and stirredfor a further 18 hours. The mixture was diluted with ether, theinsolubles removed by filtration and the solvent was removed from thefiltrate by evaporation. The residue was partitioned between ethylacetate and water, the organic phase was separated and dried (MgSO₄),and solvent was removed by evaporation. The residue was dissolved inacetone and ethereal hydrogen chloride (1.2 ml of a 3M solution) wasadded. The mixture was left to stand for 15 minutes and the precipitatedproduct was collected by filtration, washed with ether and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]quinazolinehydrochloride (54 mg, 16%). ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H);4.63(dd, 2H); 4.83(dd, 2H); 7.42(d, 1H); 7.50(s, 1H); 7.56(d, 1H);7.6-7.65(m, 3H); 8.39(s, 1H); 8.77(s, 1H); 8.80(s, 2H) MS-ESI: 441 [MH]⁺

The starting material was prepared as follows:

Sodium hydride (1.27 g of a 50% suspension in mineral oil, 26.4 mmol)was added to a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50ml) and the mixture stirred for 30 minutes.2-(2-Bromoethoxy)tetrahydropyran (5.0 g, 23.9 mmol), (J. Am. Chem. Soc.1948, 70, 4187), in DMF (5 ml) was added and the mixture heated at 80°C. for 3 hours. The reaction mixture was allowed to cool, diluted withwater and extracted with ethyl acetate. The extract was washed withwater, dried (MgSO₄) and the solvent removed by evaporation. The residuewas purified by column chromatography eluting with methylenechloride/methanol mixtures (100/0 increasing to 97/3) to give1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (1.5 g,28%). ¹H NMR Spectrum: (DMSOd₆) 1.39-1.68(m, 6H); 3.39-3.44(m, 1H);3.64-3.78(m, 2H); 3.86-3.92(m, 1H); 4.20(t, 2H); 4.64(s, 1H); 6.95(d,2H); 8.36(d, 2H) MS-ESI: 224 [MH]⁺

A solution of1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (500 mg,2.23 mmol) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heatedat 45° C. for 4 hours. The volatiles were removed by evaporation to give1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 71%) as an off-whitesolid. ¹H NMR Spectrum: (DMSOd₆) 3.70(t, 2H); 4.06(t, 2H); 6.95(d, 2H);8.37(d, 2H)

EXAMPLE 21

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(132 mg, 0.4 mmol), (prepared as described for the starting material inExample 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (96 mg,0.48 mmol) in pyridine (2 ml) was heated at reflux for 3 hours. Themixture was allowed to cool, the solvent was removed by evaporation andthe residue was partitioned between ethyl acetate and water. The organiclayer was separated, washed with water, brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/ether (70/30). Theresulting solid was crystallised from methylene chloride and methanol togive7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline(120 mg, 64%). ¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H); 3.98(s, 3H);5.35(s, 2H); 6.75(d, 1H); 7.13(d, 1H); 7.37(d, 1H); 7.45(t, 2H);7.48-7.56(m, 3H); 7.58(s, 1H); 8.54 (s, 1H); 9.65(br s, 1H) MS-ESI: 454[MH]⁺

Elemental Analysis: Found C 67.8 H 4.9 N 6.9 C₂₃H₁₉N₂O₄F 0.1 H₂ORequires C 67.7 H 4.7 N 6.9%

The starting material was prepared as follows:

A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (8 g, 35mmol), (EP 0307777 A2), and platinum(IV)oxide (174 mg) in ethanol (100ml) and ethyl acetate (70 ml) was stirred under hydrogen at 1.3atmospheres pressure for 1.5 hours. The catalyst was removed byfiltration through diatomaceous earth and the solvent removed byevaporation. The residue was purified by column chromatography elutingwith petroleum ether/ethyl acetate (7/3) to give2-fluoro-5-methoxycarbonyloxy-4-methylaniline (6.56 g, 94%) as an oilwhich crystallised. ¹H NMR Spectrum (CDCl₃): 2.09(s, 3H); 3.66(br s,2H); 3.90(s, 3H); 6.54(d, 1H); 6.83(d, 1H)

A solution of sodium nitrite (1.63 g, 23 mmol) in water (19 ml) and ice(48 g) was added dropwsie to a solution of2-fluoro-5-methoxycarbonyloxy-4-methylaniline (3.93 g, 20 mmol) in 35%sulphuric acid (48 ml) at 0° C. The reaction mixture was stirred at 0°C. for 30 minutes and a solution of copper(II)nitrate trihydrate (467 g,1.93 mol) in water (780 ml) followed by copper(II)oxide (2.65 g, 18mmol) were added. The solution was extracted with ethyl acetate, theorganic layer was washed with brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with petroleum ether/ethyl acetate (8/2) to give2-fluoro-5-methoxycarbonyloxy-4-methylphenol (2.13 g, 53%) as a yellowsolid. ¹H NMR Spectrum (CDCl₃): 2.13(s, 3H); 3.91(s, 3H); 5.11(br s,1H); 6.78(d, 1H); 6.93(d, 1H)

EXAMPLE 22

A mixture of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (470 mg, 1 mmol), 4-chloromethyl-2-methylthiazolehydrochloride (368 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) andpotassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 24hours. The mixture was allowed to cool and partitioned between ethylacetate and water. The organic layer was washed with water and brine,dried (MgSO₄) and the solvent removed by evaporation. The residue wasdissolved in methanol (15 ml) and 1M sodium hydroxide (2 ml) was addedand the mixture stirred for 30 minutes. Concentrated hydrochloric acid(0.5 ml) was added. The solvent was removed by evaporation. The residuewas purified by reverse phase HPLC eluting with a gradient (0-70%) ofmethanol in water. Concentrated hydrochloric acid (0.3 ml) was added tothe combined fractions of pure product and the solvent was removed byevaporation. The residue was triturated with acetone, collected byfiltration, washed with acetone and dried under vacuum at 55° C. to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazolinehydrochloride (225 mg, 48%). ¹H NMR Spectrum: (DMSOd₆) 2.17(s, 3H);2.69(s, 3H); 4.00(s, 3H); 4.7(br s, 1H); 5.34(s, 2H); 6.91(d, 1H); 7.1(d, 1H); 7.60(s, 1H); 7.74(s, 1H); 8.33(s, 1H); 8.79(s, 1H); 11.5(s, 1H)MS-ESI: 427 [MH]⁺

The starting material was prepared as follows:

A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (3 g, 13mmol), (EP 0307777 A2), and platinum(IV)oxide (300 mg) in ethanol (60ml) was stirred under hydrogen at 0.3 atmosphere for 1 hour. Thecatalyst was removed by filtration through diatomaceous earth and thesolvent removed by evaporation to give2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.6 g, 100%) as a solid.¹H NMR Spectrum: (CDCl₃) 2.07(s, 3H); 3.87(s, 3H); 6.52(d, 1H); 6.80(d,1H)

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(800 mg, 2.4 mmol), (prepared as described for the starting material inExample 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg,2.89 mmol) in isopropanol (20 ml) was heated at reflux for 2 hours. Themixture was allowed to cool to ambient temperature, the precipitatedsolid was collected by filtration, washed with isopropanol and driedunder vacuum to give7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (1.0 g, 77%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.2(s,3H); 3.85(s, 3H); 4.0(s, 3H); 5.37(s, 2H); 7.3-7.55(m, 8H); 8.13(s, 1H);8.86(s, 1H) MS-ESI: 464 [MH]⁺

A mixture of7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (700 mg, 1.4 mmol) and 10% palladium-on-charcoal (100 mg)in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) wasstirred under hydrogen at 1 atmosphere pressure for 1 hour. The catalystwas removed by filtration through diatomaceous earth and the solvent wasremoved by evaporation. The residue was triturated with ether, collectedby filtration and dried under vacuum to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (570 mg, 98%). ¹H NMR Spectrum: (DMSOd₆) 2.23(s, 3H);3.87(s, 3H); 4.01(s, 3H); 7.37(s, 1H); 7.45(d, 1H); 7.5(d, 1H); 8.20(s,1H); 8.77(s, 1H); 11.35(s, 1H); 11.79(s, 1H) MS-ESI: 374 [MH]⁺

EXAMPLE 23

A mixture of 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (350mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol),(prepared as described for the starting material in Example 13), inisopropanol (15 ml) was heated at reflux for 1 hour. The resultingprecipitate was collected by filtration and purified by reverse phaseHPLC using a gradient (0-75%) of methanol in water. Concentratedhydrochloric acid (0.5 ml) was added to the combined fractions of pureproduct and the solvent was removed by evaporation to give4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazolinehydrochloride (140 mg, 28%). ¹H NMR Spectrum: (DMSOd₆) 2.16(s, 3H);5.69(s, 2H); 6.19(d, 1H); 7.1 (d, 1H); 7.48(d, 1H); 7.66(dd, 1H);8.06(d, 2H); 8.84(s, 1H); 8.86(d, 1H); 8.90(d, 2H); 9.7(br s, 1H);11.71(s, 1H) MS-ESI: 377 [MH]⁺

Elemental Analysis: Found C 50.9 H 4.9 N 11.1 C₂₁H₁₇N₄O₂F 2.4 H₂O 2 HClRequires C 51.2 H 4.9 N 11.4%

The starting material was prepared as follows:

Sodium hydride (0.72 g of a 60% suspension in mineral oil, 18 mmol) wasadded to a solution of 4-hydroxymethylpyridine (4 g, 36 mmol) in THF (30ml) and the mixture heated at reflux for 15 minutes.7-Fluoro-3,4-dihydroquinazolin-4-one (1 g, 6 mmol), (J. Chem. Soc.section B 1967, 449), was added, the THF was removed by evaporation, andthe mixture was heated at 120° C. for 30 minutes. The mixture wasallowed to cool, diluted with water (40 ml) and was adjusted to pH8 withconcentrated hydrochloric acid. The resulting precipitate was collectedby filtration, washed with water, then ether and dried under vacuum togive 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (1.12 g, 71%). ¹HNMR Spectrum (DMSOd₆) 5.35(s, 2H); 7.15-7.22(m, 2H); 7.5(d, 2H); 8.05(d,1H); 8.07 (s, 1H); 8.6(d, 2H).

A mixture of 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (320 mg,1.26 mmol), DMF (1 drop) and thionyl chloride (10 ml) was heated at 60°C. for 1 hour. The volatiles were removed by evaporation, the residuewas triturated with ether, collected by filtration, washed with etherand dried under vacuum to give 4-chloro-7-(4-pyridylmethoxy)quinazolinehydrochloride (435 mg, 98%). ¹H NMR Spectrum (DMSOd₆) 5.7(s, 2H);7.32(s, 1H); 7.35(d, 1H); 8.1-8.2(m, 3H); 8.62(s,1H); 9.0(d, 2H).MS-ESI: 272 [MH]⁺

EXAMPLE 24

A solution of 1,1′-(azodicarbonyl)dipiperidine (378 mg, 1.5 mmol) inmethylene chloride (5 ml) was added dropwise to a suspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 60 mg,0.5 mmol), tributylphosphine (303 mg, 1.5 mmol) and2-(imidazol-1-yl)ethanol (67 mg, 0.6 mmol), (J. Med. Chem. 1993, 25,4052-4060), in methylene chloride (8 ml) and the mixture was stirred for3 hours at ambient temperature. Acetic acid (60 mg, 1 mmol) was addedand the solvent was removed by evaporation. The solid residue wasadsorbed on silica and purified by column chromatography eluting withmethylene chloride/methanol (9/1 followed by 8/2). The resulting whitesolid was dissolved in methylene chloride/methanol and a solution of 5Mhydrochloric acid in isopropanol was added. The solvent was removed byevaporation and the solid was triturated with ether, filtered, washedwith ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (180 mg, 74%). ¹H NMR Spectrum: (DMSOd₆) 4.01(s, 3H);4.62(t, 2H); 4.76(t, 2H); 7.44(dd, 1H); 7.48(s, 1H); 7.59(t, 1H);7.66(dd, 1H); 7.72(s, 1H); 7.84(s, 1H); 8.41(s, 1H); 8.78(s, 1H);9.22(s, 1H) MS-ESI: 414 [MH]⁺

Elemental Analysis: Found C 48.3 H 4.1 N 14.0 C₂₀H₁₇N₅O₂ClF 0.4 H₂O 2HCl Requires C 48.6 H 4.0 N 14.2%

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(1.2 g, 3.6 mmol), (prepared as described for the starting material inExample 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in isopropanol(40 ml) was heated at reflux for 1.5 hours. The mixture was allowed tocool, the precipitate was collected by filtration, washed withisopropanol then ether and dried under vacuum to give7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (1.1 3 g, 71%). m.p. 239-242° C. ¹H NMR Spectrum: (DMSOd₆)4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 1H)MS-ESI: 410 [MH]⁺

Elemental analysis: Found C 59.2 H 4.3 N 9.4 C₂₂H₁₇N₃O₂ClF HCl RequiresC 59.2 H 4.1 N 9.4%

A solution of7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (892 mg, 2 mmol) in TFA (10 ml) was heated at reflux for50 minutes. The mixture was allowed to cool and then poured on to ice.The precipitate was collected by filtration, dissolved in methanol (10ml) and basified to pH 11 with aqueous ammonia. The mixture wasconcentrated by evaporation, the resulting solid product was collectedby filtration, washed with water then ether and dried under vacuum togive 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (460mg, 72%) as a yellow solid. m.p. 141-143° C. ¹H NMR Spectrum: (DMSOd₆)3.95(s, 3H); 7.05(s, 1H); 7.35(d, 1H); 7.54-7.59(m, 2H); 7.78(s, 1H);8.29(s, 1H) MS-ESI: 320 [MH]⁺

EXAMPLE 25

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(448 mg, 1.4 mmol), (prepared as described for the starting material inExample 24), and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml)was stirred at ambient temperature for 10 minutes.4-Chloromethyl-2-methylthiazole hydrochloride (310 mg, 168 mmol) wasadded and the mixture was heated at 70° C. for 3.5 hours. The reactionmixture was allowed to cool and was partitioned between ethyl acetateand water. The organic layer was separated, washed with water, brine,dried (MgSO₄) and the solvent removed by evaporation. The solid residuewas purified by column chromatography eluting with a mixture ofmethylene chloride/acetonitrile/methanol (50/45/5 followed by 50/40/10).The resulting purified solid was dissolved in methylenechloride/methanol and a solution of 5M hydrogen chloride in isopropanol(1 ml) was added. Partial evaporation led to the precipitation of awhite solid. This solid was collected by filtration and dried undervacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazolinehydrochloride (240 mg, 35%). m.p. 220-225° C. ¹H NMR Spectrum: (DMSOd₆)2.68(s, 3H); 4.0(s, 3H); 5.36(s, 2H); 7.46(dd, 1H); 7.54(s, 1H); 7.61(t,1H); 7.7(d, 1H); 7.71(s, 1H); 8.26(s, 1H); 8.83(s, 1H) MS-ESI: 431 [MH]⁺

Elemental Analysis: Found C 49.3 H 4.0 N 11.3 C₂₀H₁₆N₄O₂ClFS 0.3 H₂ORequires C 48.9 H 3.7 N 11.4% 1.5 HCl

EXAMPLE 26

Using an analogous procedure to that described in Example 25,4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (224 mg, 0.7mmol), (prepared as described for the starting material in Example 24),and 2-chloromethyl-1-methylimidazole hydrochloride (140 mg, 0.8 mmol)were combined to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazolinehydrochloride (150 mg, 44%). ¹H NMR Spectrum: (DMSOd₆) 3.94(s, 3H);4.02(s, 3H); 5.69(s, 2H); 7.44(dd, 1H); 7.6(t, 1H); 7.64(s, 1H);7.67(dd, 1H); 7.72(d, 1H); 7.81(d, 1H); 8.46(s, 1H); 8.81(s, 1H) MS-ESI:414 [MH]⁺

Elemental Analysis: Found C 48.7 H 4.6 N 13.6 C₂₀H₁₇N₅O₂ClF 0.5 H₂O 2HCl Requires C 48.8 H 4.3 N 13.7% 0.25 isopropanol

EXAMPLE 27

A mixture of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7hydroxy-6-methoxyquinazolinehydrochloride (470 mg, 1 mmol), (prepared as described for the startingmaterial in Example 22), 2-chloromethyl-1-methylimidazole hydrochloride(335 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassiumiodide (20 mg) in DMF (15 ml) was heated at 60° C. for 2 hours. Themixture was allowed to cool and partitioned between ethyl acetate andwater. The organic layer was separated, washed with water and brine,dried (MgSO₄) and the solvent removed by evaporation. The crude productwas dissolved in methanol (20 ml), 2M sodium hydroxide (1 ml) was addedand the mixture stirred for 15 minutes. Concentrated hydrochloric acid(0.5 ml) was added and the solvent was removed by evaporation. The crudeproduct was purified by reverse phase chromatography eluting withmethanol/water (1/1). Concentrated hydrochloric acid (0.3 ml) was addedto the combined fractions containing the pure product and the solventwas removed by evaporation to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazolinehydrochloride (100 mg, 21%). ¹H NMR Spectrum: (DMSOd₆) 2.17(s, 3H);3.95(s, 3H); 4.01(s, 3H); 5.70(s, 2H); 6.92(d, 1H); 7.12(d, 1H); 7.63(s,1H); 7.77(s, 1H); 7.83(s, 1H); 8.43(s, 1H); 8.82(s, 1H); 9.7(br s, 1H);11.62(br s, 1H) MS-ESI: 410 [MH]⁺

EXAMPLE 28

Using an analogous procedure to that described in Example 27,4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (470 mg 1.14 mmol), (prepared as described for thestarting material in Example 22), and 2-acetamido-4-chloromethylthiazole(381 mg, 1.68 mmol) were combined to give7-((2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline(135 mg, 25%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.16(s, 3H); 2.19(s,3H); 4.00(s, 3H); 5.33(s, 2H); 6.91(d, 1H); 7.12(d, 1H); 7.33(s, 1H);7.49(s, 1H); 8.16(s, 1H); 8.82(s, 1H) MS-ESI: 470 [MH]⁺

Elemental Analysis: Found C 51.5 H 4.5 N 13.3 C₂₂H₂₀N₅O₄FS 0.4 H₂O0.95HCl Requires C 51.7 H 4.3 N 13.7%

EXAMPLE 29

A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(169 mg, 0.5 mmol), (prepared as described for the starting material inExample 1), and 4-chloro-2-fluoro-5-hydroxyaniline (97 mg, 0.6 mmol),(EP 061741 A2), in isopropanol (5 ml) was heated at reflux for 2 hours.The resulting precipitate was collected by filtration, washed withisopropanol and ether and dried under vacuum to give7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazolinehydrochloride (197 mg, 85%). ¹H NMR Spectrum: (DMSOd₆) 4.0(s, 3H);5.36(s, 2H); 7.15(d, 1H); 7.4-7.5(m, 4H); 7.52(s, 1H); 7.54(d, 2H);8.23(s, 1H); 8.8(s, 1H); 10.6(s, 1H); 11.39(br s, 1H) MS-ESI: 426 [MH]⁺

Elemental Analysis: Found C 57.1 H 4.2 N 8.9 C₂₂H₁₇N₃O₃ClF 0.15H₂O 1HClRequires C 56.8 H 4.0 N 9.0% 0.4 isopropanol

EXAMPLE 30

1,1′-(Azodicarbonyl)dipiperidine (1.06 g, 4.2 mmol) in methylenechloride (15 ml) was added dropwise to a solution of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4mmol), (prepared as described for the starting material in Example 24),tributylphosphine (848 mg, 4.2 mmol) and 4-(3-hydroxypropyl)pyridine(322 mg, 2.4 mmol) in methylene chloride (15 ml) and the mixture stirredfor 3 hours at ambient temperature. Acetic acid (126 mg, 2.1 mmol) wasadded and the solvent was removed by evaporation. The residue waspurified by column chromatography eluting with methylenechloride/methanol (95/5). The purified product was triturated withether, the resulting solid collected and dissolved in methylene chloride(20 ml). 5M Hydrogen chloride in isopropanol solution (0.7 ml) wasadded, the solution was diluted with isopropanol (5 ml) and concentratedby evaporation to a total volume of 4 ml. Ether was added and theresulting solid was collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazolinehydrochloride (520 mg, 73%). ¹H NMR Spectrum: (DMSOd₆) 2.30(m, 2H);3.09(t, 2H); 3.97(s, 3H); 4.27(t, 2H); 7.42(s, 1H); 7.44(d, 1H); 7.59(t,1H); 7.67(dd, 1H); 7.95(d, 2H); 8.34(s, 1H); 8.8(s, 1H); 8.82(d, 2H)MS-ESI: 439 [MH]⁺

Elemental Analysis: Found C 53.6 H 4.8 N 10.7 C₂₃H₂₀N₄O₂ClF 0.5H₂O 2HClRequires C 53.1 H 4.6 N 10.6% 0.1 isopropanol

EXAMPLE 31

2M Aqueous sodium hydroxide (1.5 ml mmol) was added to a solution of4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline(1.28 g, 2.5 mmol) in methanol (13 ml) and the mixture stirred for 2hours at ambient temperature. Water was added and the mixture wasadjusted to pH7 with 2M hydrochloric acid. The resulting precipitate wascollected by filtration, washed with water and dried under vacuum. Thissolid was dissolved in methylene chloride (30 ml) and methanol (5 ml)and a solution of 5M hydrogen chloride in isopropanol (2.5 ml) wasadded. The solution was diluted with isopropanol and concentrated undervacuum to a total volume of 10 ml. The resulting solid was collected byfiltration, washed with isopropanol and then ether and dried undervacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazolinehydrochloride (924 mg, 70%). ¹H NMR Spectrum: (DMSOd₆) 2.3(t, 2H);3.12(t, 2H); 4.0(s, 3H); 4.28(t, 2H); 7.18(d, 1H); 7.4(s, 1H); 7.52(d,1H); 7.95(d, 2H); 8.32(s, 1H); 8.82(s, 1H); 8.84(d, 2H); 10.65(s, 1H);11.65(br s, 1H) MS-ESI: 455 [MH]⁺

Elemental Analysis: Found C 51.9 H 4.5 N 10.7 C₂₃H₂₀N₄O₃ClF 0.55H₂O1.9HCl Requires C 51.5 H 4.7 N 10.5%

The starting material was prepared as follows:

1,1′-(Azodicarbonyl)dipiperidine (2.52 g, 10 mmol) in methylene chloride(10 ml) was added dropwise to a solutionof4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (1.38 g, 3.5 mmol), prepared as described for the startingmaterial in Example 22), tributylphosphine (2 g, 10.5 mmol) and4-(3-hydroxypropyl)pyridine (720 mg, 5.25 mmol) in methylene chloride(25 ml) and the mixture stirred for 2.5 hours at ambient temperature.The solvent was removed by evaporation and the residue was trituratedwith petroleum ether. The solid product was collected by filtration andpurified by column chromatography eluting with methylenechloride/methanol (95/5) to give4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline(1.2 g, 67%). ¹H NMR Spectrum: (DMSOd₆) 2.18(m, 2H); 2.84(t, 2H);3.90(s, 3H); 3.97(s, 3H); 4.2(t, 2H); 7.21(s, 1H); 7.3(d, 2H);7.72-7.82(m, 3H); 8.41(s, 1H); 8.47(d, 2H); 9.67(s, 1H) MS-ESI: 513[MH]⁺

EXAMPLE 32

2M Aqueous sodium hydroxide (0.3 ml, 6 mmol) was added to a solution of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline(257 mg, 5.5 mmol) in methanol (5 ml) and the mixture stirred for 1 hourat 40° C. Water and 1M hydrochloric acid (0.6 ml) were added and themixture concentrated to half volume by evaporation. The resulting solidwas collected by filtration, dissolved in methylene chloride/methanoland a solution of 7M hydrogen chloride in isopropanol (0.4 ml) wasadded. The volatiles were removed by evaporation, the solid residue wastriturated with ether, collected by filtration and dried under vacuum togive4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (160 mg, 60%). m.p. 195-220° C. ¹H NMR Spectrum: (DMSOd₆)2.16(s, 3H); 4.0(s, 3H); 4.63(t, 2H); 4.76(t, 2H); 6.90(d, 1H); 7.1(d,1H); 7.44(s, 1H); 7.72(s, 1H); 7.83(s, 1H); 8.31(s, 1H); 8.76(s, 1H);9.20(s, 1H); 9.7(s, 1H); 11.4(br s, 1H) MS-ESI: 410 [MH]⁺

Elemental Analysis: Found C 52.3 H 5.1 N 13.7 C₂₁H₂₀N₅O₃F 0.3H₂O 1.9HClRequires C 52.3 H 4.9 N 14.1% 0.22 isopropanol

The starting material was prepared as follows:

Diethyl azodicarboxylate (160 mg, 1.4 mmol) was added to a solution of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (261 mg, 0.7 mmol), (prepared as described for thestarting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol)and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol), (J. Med. Chem. 1993,25, 4052-4060), in methylene chloride (5 ml) and the mixture stirred for1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was addedand the solvent was removed by evaporation. The residue was trituratedwith ether, the solid collected by filtration, dried under vacuum andpurified by chromatography eluting with methylene chloride/methanol (9/1followed by 8/2) to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline(250 mg, 76%).

EXAMPLE 33

A 1M solution of tetrabutylammonium fluoride in THF (560 μl, 0.56 mmol)was added to a suspension of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline(186 mg, 0.28 mmol) in THF (5 ml) and the mixture stirred at 40° C. for1 hour. Water was added and the organic solvent was removed byevaporation. The resulting precipitate was collected by filtration,washed with water and dried by azeotroping with ethanol. The solid wasdissolved in methylene chloride/methanol and a solution of 5M hydrogenchloride in isopropanol (0.5 ml) was added. The volatiles were removedby evaporation and the residue was dissolved in isopropanol (1 ml) andether was added. The resulting precipitate was collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (110 mg, 78%). ¹H NMR Spectrum: (DMSOd₆) 4.01(s, 3H);4.63(t, 2H); 4.75(t, 2H); 7.17(d, 1H); 7.46(s, 1H); 7.51(d, 1H); 7.72(s,1H); 7.83(s, 1H); 8.36(s, 1H); 8.79(s, 1H); 9.21(s, 1H); 10.63(br s,1H); 11.6(br s, 1H) MS-ESI: 430 [MH]⁺

Elemental Analysis: Found C 45.7 H 3.9 N 12.8 C₂₀H₁₇N₅O₃ClF 1H₂O 2HClRequires C 45.8 H 4.1 N 13.1% 0.09 isopropanol 0.09 methylene chloride

The starting material was prepared as follows:

A mixture of7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline(2.35 g, 7 mmol), (prepared as described for Example 29), imidazole (1.2g, 17.5 mmol), t-butyldiphenylsilylchloride (2.1 g, 7.7 mmol) and4-(dimethylamino)pyridine (20 mg, 0.16 mmol) in DMF (10 ml) was stirredfor 2 hours at ambient temperature. Water (100 ml) and ethyl acetate (30ml) were added, the resulting precipitate was collected by filtration,washed with water and dried under vacuum to give7-benzyloxy-4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxyquinazoline(2 g, 43%). ¹H NMR spectrum (DMSOd₆) 1.09(s, 9H); 3.86(s, 3H); 5.25(s,2H); 7.04(d, 1H); 7.23(s, 1H); 7.32-7.5(m, 11H); 7.58(d, 1H);7.65-7.72(m, 5H); 8.1(s, 1H); 9.25 (br s, 1H) MS-ESI: 663 [MH]⁺

A mixture of7-benzyloxy-4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxyquinazoline(2 g, 3 mmol) and 10% palladium-on-charcoal catalyst (400 mg) in DMF (20ml), methanol (20 ml) and ethyl acetate (20 ml) was stirred underhydrogen at 1.7 atmospheres pressure for 2 hours. The catalyst wasremoved by filtration and the solvent removed by evaporation. Theresidue was purified by column chromatography eluting with methylenechloride/methanol (95/5 followed by 90/10). The purified product wastriturated with ether, collected by filtration and dried under vacuum togive4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(1.65 g, 95%). ¹H NMR spectrum (DMSOd₆) 1.09(s, 9H); 3.87(s, 3H);7.00(s, 1H); 7.07(d, 1H); 7.4-7.5(m, 6H); 7.55(d, 1H); 7.62(s, 1H);7.7(m, 4H); 8.04(s, 1H); 9.15(br s, 1H); 10.34(br s, 1H

Diethyl azodicarboxylate (174 mg, 1 mmol) was added to a solution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(288 mg, 0.5 mmol), triphenylphosphine (262 mg, 1 mmol) and2-(imidazol-1-yl)ethanol (62 mg, 0.55 mmol), (J. Med. Chem. 1993, 25,4052-4060), in methylene chloride (5 ml) and the mixture stirred for 1hour at ambient temperature. Acetic acid (30 mg, 0.5 mmol) was added andthe volatiles were removed by evaporation. The residue was trituratedwith ether, the solid collected by filtration and dried under vacuum togive4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline(186 mg, 55%). MS-ESI: 668 [MH]⁺

EXAMPLE 34

A suspension of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline(300 mg, 0.63 mmol) and 2M aqueous sodium hydroxide (0.38 ml, 0.76 mmol)in methanol (6 ml) was stirred at ambient temperature for 2 hours. Waterwas added and the mixture adjusted to pH7 with 2M hydrochloric acid. Theprecipitate was collected by filtration, washed with water, and driedunder vacuum. The solid was dissolved in methylene chloride/methanol anda 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added.The mixture was diluted with isopropanol, and the methylene chloride andmethanol solvents were removed by evaporation. The resulting precipitatewas collected by filtration, washed with methylene chloride and driedunder vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazolinehydrochloride (270 mg, 94%). ¹H NMR Spectrum: (DMSOd₆) 2.16(s, 3H);3.5(t, 2H); 3.99(s, 3H); 4.57(t, 2H); 6.89(d, 1H); 7.12(d, 1H); 7.44(s,1H); 7.98(d, 2H); 8.24(s, 1H); 8.78(s, 1H); 8.81(d, 2H); 9.7(br s, 1H);11.38(br s, 1H) MS-ESI: 421 [MH]⁺

Elemental Analysis: Found C 55.5 H 5.3 C₂₃H₂₁N₄O₃F 0.3H₂O 1HCl RequiresC 55.6 H 5.1 0.3 isopropanol

The starting material was prepared as follow:

Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added to a suspension of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (261 mg, 0.7 mmol), (prepared as described for thestarting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol)and 2-(4-pyridyl)ethanol (104 mg, 0.84 mmol), (Zhur. Obshchei. Khim.1958, 28, 103-110), in methylene chloride and the mixture stirred for 30minutes at ambient temperature. The solvent was removed by evaporation.The residue was suspended in ether and the ether then decanted. Theresulting crude oil was purified by column chromatography eluting withmethylene chloride/methanol (90/10) to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline(300 mg, 90%). ¹H NMR Spectrum: (DMSOd₆) 2.18(s, 3H); 3.16(t, 2H);3.84(s, 3H); 3.92(s, 3H); 4.44(t, 2H); 7.24(s, 1H); 7.29(d, 1H); 7.40(d,2H); 7.79(s, 1H); 8.35(s, 1H); 8.49(d, 2H); 9.51(s, 1H) MS-ESI: 501[MNa]⁺

EXAMPLE 35

Using an analogous procedure to that described in Example 34,4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline(220 mg, 0.47 mmol) was treated with 2M aqueous sodium hydroxide (0.47ml) to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazolinehydrochloride 180 mg, 86%). ¹H NMR Spectrum: (DMSOd₆) 2.17(s, 3H);3.98(s, 3H); 5.34(s, 2H); 6.89(d, 1H); 7.15(d, 1H); 7.27(d, 1H); 7.47(s,1H); 7.65(dd, 1H); 7.75(s, 1H); 8.18(s, 1H); 8.77(s, 1H); 9.7(br s, 1H)MS-ESI: 412 [MH]⁺

Elemental Analysis: Found C 55.5 H 4.5 N 9.0 C₂₁H₁₈N₃O₃FS 0.2H₂O 1HClRequires C 55.9 H 4.4 N 9.2% 0.09 isopropanol

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example 34,4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (261 mg, 0.7 mmol), (prepared as described for thestarting material in Example 22), was combined with 3-thiophenemethanol(96 mg, 0.84 mmol) to give, after purification by flash chromatographyeluting with methylene chloride/methanol (98/2),4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline(220 mg, 67%). ¹H NMR Spectrum: (DMSOd₆) 2.18(s, 3H); 3.85(s, 3H);3.93(s, 3H); 5.27(s, 2H); 7.23(d, 1H); 7.30(d, 1H); 7.32(s, 1H); 7.40(d,1H); 7.59(dd, 1H); 7.66(s, 1H); 7.81(s, 1H); 8.35(s, 1H); 9.53(s, 1H)MS-ESI: 492 [MNa]⁺

EXAMPLE 36

A mixture of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (187 mg, 0.75 mmol), (prepared as described for thestarting material in Example 22), 4-bromomethylbenzonitrile (147 mg,0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (5 ml) washeated at 50° C. for 1 hour. Methanol (5 ml) and potassium carbonate(138 mg, 1 mmol) were added and the mixture stirred at 65° C. for 2hours. The solvent was removed by evaporation, water was added to theresidue and the mixture adjusted to pH7 with 2M hydrochloric acid. Theresulting precipitate was collected by filtration, washed with water anddried under vacuum. The solid was purified by column chromatographyeluting with methylene chloride/methanol (95/5). The purified productwas triturated with ether, collected by filtration and dried. The solidwas dissolved in methylene chloride/isopropanol and a 5M solution ofhydrogen chloride in isopropanol (0.5 ml) was added. The mixture wasconcentrated by evaporation and the resulting precipitate collected byfiltration, washed with methylene chloride and dried under vacuum togive7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (60 mg, 25%). m.p. 265-270° C. ¹H NMR Spectrum: (DMSOd₆)2.17(s, 3H); 4.02(s, 3H); 5.47(s, 2H); 6.89(d, 1H); 7.11(d, 1H); 7.38(s,1H); 7.71(d, 2H); 7.93(d, 2H); 8.23(s, 1H); 8.75(s, 1H); 9.67(s, 1H);11.24(br s, 1H) MS-ESI: 431 [MH]⁺

Elemental Analysis: Found C 61.2 H 4.5 N 11.7 C₂₄H₁₉N₄O₃F 0.1H₂O 1HClRequires C 61.5 H 4.3 N 12.0%

EXAMPLE 37

Diethyl azodicarboxylate (315 μl, 2 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(319.5 mg, 1 mmol), (prepared as described for the starting material inExample 24), triphenylphosphine (524 mg, 2 mmol) and2-(4-pyridyl)ethanol (160 mg, 1.25 mmol), (Zhur. Obshchei. Khim. 1958,28, 103-110), in methylene chloride (7 ml). The mixture was stirred for1 hour at ambient temperature and the solvent was removed byevaporation. The residue was triturated with ether, the solid collectedby filtration and purified by column chromatography eluting withmethylene chloride/acetonitrile/methanol (85/10/5). The purified solidproduct was dissolved in a mixture of methylene chloride (50 ml) andmethanol (50 ml) and 5M hydrochloric acid in isopropanol (0.5 ml) wasadded. After diluting with isopropanol (20 ml), the mixture wasconcentrated by evaporation. The precipitated solid was collected byfiltration and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazolinehydrochloride (125 mg, 25%). m.p. 189-191° C. ¹H NMR Spectrum: (DMSOd₆;CF₃COOD) 3.55(t, 2H); 3.99(s, 3H); 4.64(t, 2H); 7.46(s, 1H); 7.48(d,1H); 7.62(t, 1H); 7.67(dd, 1H); 8.16(d, 2H); 8.17(s, 1H); 8.88(s, 1H);8.94(d, 1H) MS-ESI: 425 [MH]⁺

Elemental Analysis: Found C 52.0 H 4.3 N 11.1 C₂₂H₁₈N₄O₂ClF 0.5H₂O1.95HCl Requires C 52.3 H 4.2 N 11.1%

EXAMPLE 38

3-(Chloromethyl)pyridine hydrochloride (328 mg, 2 mmol) was added to amixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(319.5 mg, 1 mmol), (prepared as described for the starting material inExample 24), potassium carbonate (442 mg, 3.2 mmol) and potassium iodide(33 mg, 0.2 mmol) in DMF (25 ml) at ambient temperature and the reactionmixture then heated at 80° C. for 2.5 hours. The mixture was allowed tocool and the volatiles were removed by evaporation. The residue wasdissolved in a mixture of ethyl acetate (19 ml) and methanol (1 ml) andthe insolubles removed by filtration. The solvent was removed from thefiltrate by evaporation and the residue was purified by columnchromatography eluting with methylene chloride/acetonitrile/methanol(50/45/5). The purified product was dissolved in hot methylene chlorideand saturated ethereal hydrogen chloride was added. The mixture wasconcentrated to half volume by evaporation, the resulting precipitatewas collected by filtration and dried under vacuum at 70° C. to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((3-pyridyl)methoxy)quinazolinehydrochloride(103 mg, 25%). m.p. 216-221° C. ¹H NMR Spectrum: (DMSOd₆)4.03(s, 3H); 5.48(s, 2H); 7.47(d, 1H); 7.54(s, 1H); 7.65(t, 1H);7.7-7.8(m, 2H); 8.25(d, 1H); 8.35(s, 1H); 8.75(d, 1H); 8.84(s, 1H);8.90(s, 1H); 11.65(br s, 1H) MS-ESI: 411 [MH]⁺

Elemental Analysis: Found C 51.9 H 4.2 N 11.4 C₂₁H₁₆N₄O₂ClF 0.8H₂O1.6HCl Requires C 52.2 H 4.0 N 11.6%

EXAMPLE 39

Using an analogous procedure to that described in Example 38,4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1mmol), (prepared as described for the starting material in Example 24),was reacted with 2-(chloromethyl)pyridine hydrochloride (310 mg, 1.9mmol) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-pyridyl)methoxy)quinazoline(146 mg, 33%). m.p. 215-218° C. ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H);5.4(s, 2H); 7.3(s, 1H); 7.32-7.42(m, 2H); 7.52-7.62(m, 3H); 7.85(s, 1H);7.90(t, 1H); 8.35(s, 1H); 8.65(d, 1H); 9.6(s, 1H) MS-ESI: 411 [MH]⁺

Elemental Analysis: Found C 59.7 H 3.9 N 13.1 C₂₁H₁₆N₄O₂ClF 0.5H₂ORequires C 60.1 H 4.1 N 13.3%

EXAMPLE 40

Diethyl azodicarboxylate (128 μl, 1.5 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(250 mg, 0.78 mmol), (prepared as described for the starting material inExample 24), triphenylphosphine (410 mg, 1.5 mmol) and2-(1-methylimidazol-2-yl)ethanol (147 mg, 1.15 mmol), (EP 0675112 A1),in methylene chloride (4 ml) and the mixture was stirred for 30 minutesat ambient temperature. Further triphenylphosphine (143 mg, 0.52 mmol)and diethyl azodicarboxylate (85 μl, 1 mmol) were added and the mixturestirred for 1 hour at ambient temperature. The solid product wascollected by filtration and washed with methylene chloride. The solidwas dissolved in a mixture of methylene chloride (25 ml) and methanol(25 ml), and a solution of 2.9M ethereal hydrogen chloride (2 ml) wasadded. The mixture was concentrated by evaporation and the resultingprecipitate was collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazolinehydrochloride (133 mg, 34%). m.p. 224-229° C. ¹H NMR Spectrum: (DMSOd₆)3.62(t, 2H); 3.94(s, 3H); 4.0(s, 3H); 4.59(t, 2H); 7.43(d, 1H); 7.46(s,1H); 7.6(t, 1H); 7.6-7.7(m, 3H); 8.41(s, 1H); 8.78(s, 1H); 11.75(br s,1H) MS-ESI: 428 [MH]⁺

Elemental Analysis: Found C 48.8 H 4.4 N 13.4 C₂₁H₁₉N₅O₂ClF 1H₂O 2HClRequires C 48.6 H 4.5 N 13.5%

EXAMPLE 41

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline319.5 mg, 1 mmol), (prepared as described for the starting material inExample 24), potassium carbonate (414 mg, 3 mmol), potassium iodide (16mg, 0.1 mmol) and 4-chloromethylpyrimidine (257 mg, 2 mmol) in DMF (20ml) was heated at 80° C. for 2 hours. The solvent was removed byevaporation and the residue was triturated with water. The solid wascollected by filtration and dried under vacuum. The solid was purifiedby column chromatography eluting with methylene chloride/methanol(95/5). The purified white solid was suspended in methanol (25 ml) and asolution of 7.5M hydrogen chloride in methanol (20 ml) was added. Theresulting solid product was collected by filtration, washed withmethanol and then pentane and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((pyrimidin-4-yl)methoxy)quinazolinehydrochloride (172 mg, 42%). m.p. 237-239° C. ¹H NMR Spectrum: (DMSOd₆;CF₃COOD) 4.07(s, 3H); 5.53(s, 2H); 7.40(s, 1H); 7.46(dd, 1H); 7.65(t,1H); 7.68-7.72(m, 2H); 8.26(s, 1H); 8.85(s, 1H); 8.91(d, 1H); 9.25(s,1H) MS-ESI: 412 [MH]⁺

Elemental Analysis: Found C 49.5 H 3.6 N 14.1 C₂₀H₁₅N₅O₂ClF 0.5H₂O1.85HCl Requires C 49.2 H 3.7 N 14.3%

The starting material was prepared as follows:

A solution of 4-methylpyrimidine (2 g, 21.2 mmol), N-chlorosuccinimide(4.26 g, 31.9 mmol) and benzoyl peroxide (500 mg, 2.1 mmol) in carbontetrachloride (100 ml) was heated at 80° C. for 2 hours. The mixture wasallowed to cool, the insolubles were removed by filtration and thesolvent was removed from the filtrate by evaporation. The residue waspurified by column chromatography eluting with methylene chloride togive 4-chloromethylpyrimidine (257 mg, 10%). ¹H NMR Spectrum: (DMSOd₆)4.81(s, 2H); 7.70(d, 1H); 8.88(d, 1H); 9.21(s, 1H)

EXAMPLE 42

2M Aqueous sodium hydroxide solution (900 μl) was added to a solution of4-(3-acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline(290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml)and the mixture stirred for 25 minutes at ambient temperature. Thesolvent was removed by evaporation and the residue was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water and brine, dried (MgSO₄) and the solvent removed byevaporation. The solid residue was purified by column chromatographyeluting with methylene chloride/methanol (97/3 and 95/5). The purifiedwhite solid was suspended in methanol (20 ml) and a solution of 7.5Mhydrochloric acid in methanol (2 equivalents) was added. The solid wascollected by filtration, washed with methanol and then pentane and driedunder vacuum at 50° C. to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazolinehydrochloride (106 mg, 37%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.17(s,3H); 4.04(s, 3H); 4.15(s, 3H); 6.01(s, 2H); 7.0(dd, 1H); 7.11(d, 1H);7.18(d, 1H); 7.6-7.75(m, 3H); 7.89(d, 1H); 8.05(d, 1H); 8.27(s, 1H);8.86(s, 1H) MS-ESI: 469 [MNa]⁺

The starting material was prepared as follows:

A solution of 1-methylbenzimidazole (2.5 g, 19 mmol), (J. Chem. Soc.1929, 2820-2828), and paraformaldehyde (2 g) was heated at 165° C. for30 minutes. Further paraformaldehyde (1 g) was added and heatingcontinued for 2 hours. The mixture was allowed to cool and was purifiedby column chromatography eluting with methylene chloride, followed bymethylene chloride/methanol (95/5) to give2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 45%). ¹H NMR Spectrum:(DMSOd₆) 3.84(s, 3H); 4.73(s, 2H); 5.57(br s, 1H); 7.19(t, 1H); 7.25(t,1H); 7.54(d, 1H); 7.60(d, 1H) MS-ESI: 185 [MNa]⁺

A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, 6.7 mmol) inthionyl chloride (10 ml) was stirred at ambient temperature for 15minutes and then heated at reflux for 15 minutes. The volatiles wereremoved by evaporation and the residue purified by column chromatographyeluting with methylene chloride/methanol (95/5) to give2-chloromethyl-1-methylbenzimidazole (506 mg, 36%). ¹H NMR Spectrum:(DMSOd₆; CF₃COOD) 4.07(s, 3H); 5.38(s, 2H); 7.6-7.7(m, 2H); 7.9(d, 1H);8.05(dd, 1H) MS-ESI: 181 [MH]⁺

A mixture of4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (240 mg, 0.64 mmol), (prepared as described for thestarting material in Example 1), potassium carbonate (310 mg, 2.25mmol), potassium iodide (10 mg, 0.064 mmol) and2-chloromethyl-1-methylbenzimidazole (153 mg, 0.7 mmol) in DMF (12 ml)was heated at 65° C. for 3 hours. Further2-chloromethyl-1-methylbenzimidazole (90 mg, 0.41 mmol) and potassiumcarbonate (165 mg, 1.2 mmol) were added and heating continued for 2hours. The solvent was removed by evaporation and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was triturated with water and thesolid product collected by filtration, washed with ether and dried undervacuum to give4-(3-acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzoimidazol-2-yl)methoxy)quinazoline(292 mg, 95%). MS-ESI: 506 [MNa]⁺

EXAMPLE 43

2M Aqueous sodium hydroxide solution (700 μl, 1.4 mmol) was added to asuspension of7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline(360 mg, 0.7 mmol) in methanol (10 ml) cooled at 5° C. and the mixturewas then stirred for 30 minutes at ambient temperature. The solvent wasremoved by evaporation, the residue diluted with water (10 ml) and themixture adjusted to pH7 with 1M hydrochloric acid. The resulting solidwas collected by filtration, washed with water and ether, and driedunder vacuum. This solid was dissolved in methanol (5 ml) and a 7Msolution of hydrogen chloride in methanol (3 ml) was added. Theprecipitate was collected by filtration, washed with methanol and driedunder vacuum to give7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (273 mg, 74%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.18(s,3H); 2.50(s, 3H); 4.04(s, 3H); 5.42(s, 2H) 6.9(d, 1H); 7.12(d, 1H);7.35(s, 1H); 7.38(s, 1H); 7.42(s, 1H); 8.21(s, 1H); 8.81(s, 1H) MS-ESI:455 [MH]⁺

Elemental Analysis: Found C 49.8 H 4.8 N 10.0 C₂₃H₂₀N₄O₃ClF 1.5H₂O1.9HCl Requires C 50.1 H 4.6 N 10.2%

The starting material was prepared as follows:

A solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid (2 g, 12 mmol)in ethanol (100 ml) and concentrated sulphuric acid (10 ml) was heatedat reflux for 2 hours. The volatiles were removed by evaporation and theresidue was dissolved in methylene chloride. The solution was washedwith a saturated aqueous sodium hydrogen carbonate solution and brine,dried (MgSO₄) and the solvent removed by evaporation. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1/9) to give ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (2 g,86%). ¹H NMR Spectrum: (CDCl₃) 1.41(t, 3H); 2.6(s, 3H); 4.40(q, 2H);7.63(s, 1H); 7.69(s, 1H) MS-ESI: 200 [MH]⁺

Elemental Analysis: Found C 54.4 H 5.3 N 7.0 C₉H₁₀NO₂Cl Requires C 54.1H 5.0 N 7.0%

Lithium aluminium hydride (350 mg, 9.26 mmol) was added in portions to asolution of ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (1.85 g, 9.26mmol) in THF (40 ml) cooled at 0° C. The mixture was stirred for 15minutes at 0° C. and acetic acid (2 ml) was added. The mixture waspartitioned between ethyl acetate and water and the aqueous layer wasadjusted to pH7.5 with 5 % aqueous sodium hydrogen carbonate solution.The organic layer was separated, washed with water and brine, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography eluting with ethyl acetate/petroleum ether(35/65) to give 2-chloro-4-hydroxymethyl-6-methylpyridine (1.28 g, 88%).¹H NMR Spectrum: (CDCl₃) 1.92(t, 1H); 2.53(s, 3H); 4.70(d, 2H); 7.06(s,1H); 7.16(s, 1H) MS-ESI: 157 [MH]⁺

Elemental Analysis: Found C 53.1 H 5.3 N 8.7 C₇H₈NOCl Requires C 53.3 H5.1 N 8.9%

Diethyl azodicarboxylate (296 μl, 1.88 mmol) was added dropwise to asolution of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (350 mg, 0.94 mmol), (prepared as described for thestarting material in Example 22), triphenylphosphine (492 mg, 1.88 mmol)and 2-chloro-4-hydroxymethyl-6-methylpyridine (178 mg, 1.12 mmol) inmethylene chloride (30 ml) and the mixture stirred for 30 minutes atambient temperature. The solvent was removed by evaporation and theresidue was purified by column chromatography eluting with ethylacetate/methylene chloride (75/25). The purified product was trituratedwith ether, the solid collected by filtration, washed with ether anddried under vacuum to give7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline(373 mg, 78%). ¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H); 2.5(s, 3H);3.85(s, 3H); 3.98(s, 3H); 5.35(s, 2H) 7.25(s, 1H); 7.3(d, 1H); 7.35(s,1H); 7.4(m, 2H); 7.85(s, 1H); 8.35(s, 1H); 9.58(1H) MS-ESI: 513 [MH]⁺

EXAMPLE 44

A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline(112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and4-(chloromethyl)pyridine hydrochloride (59 mg, 0.36 mmol) in DMF (2 ml)was heated at 80° C. for 1 hour. The mixture was allowed to cool andpartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (95/5) to give4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline(115 mg, 80%). m.p. 197-198° C. ¹H NMR Spectrum: (DMSOd₆) 4.03(s, 3H);5.46(s, 2H); 7.45(d, 1H); 7.49(s, 1H); 7.5(d, 2H); 7.58(t, 1H); 7.62(s,1H); 7.72(dd, 1H); 8.58(s, 1H); 8.65(d, 2H) MS-ESI: 412 [MH]⁺

Elemental Analysis: Found C 59.5 H 3.9 N 9.6 C₂₁H₁₅N₃O₃ClF 0.8H₂ORequires C 59.2 H 3.9 N 9.9%

The starting material was prepared as follows:

4-Chloro-2-fluoro-phenol (264 mg, 1.8 mmol) was added to a solution of7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (506 mg, 1.5mmol), (prepared as described for the starting material in Example 1),in pyridine (8 ml) and the mixture heated at reflux for 45 minutes. Thesolvent was removed by evaporation and the residue partitioned betweenethyl acetate and water. The organic layer was washed with 0.1Mhydrochloric acid, water and brine, dried (MgSO₄) and the solventremoved by evaporation. The solid residue was triturated with petroleumether and the crude product collected by filtration and purified byflash chromatography eluting with methylene chloride/ether (9/1) to give7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (474 mg,77%) as a cream solid. m.p. 179-180° C. ¹H NMR Spectrum: (DMSOd₆)3.99(s, 3H); 5.36(s, 3H); 7.35-7.5(m, 4H); 7.55-7.65(m, 5H); 7.72(d,1H); 8.6(s, 1H) MS-ESI: 411 [MH]⁺

Elemental analysis: Found C H 4.1 N 63.4 6.8 C₂₂H₁₆ClFN₂O₃0.06H₂O0.05CH₂Cl₂ Requires C H 3.9 N 63.6 6.7%

A solution of7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg,1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The mixturewas diluted with toluene and the volatiles removed by evaporation. Theresidue was triturated with methylene chloride, collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg,90%). ¹H NMR Spectrum: (DMSOd₆) 4.0(s, 3H); 7.27(s, 1H); 7.43(dd, 1H);7.56(t, 1H); 7.57(s, 1H); 7.72(dd, 1H); 8.5(s, 1H) MS-ESI: 321 [MH]⁺

EXAMPLE 45

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(320 mg, 1 mmol), (prepared as described for the starting material inExample 24), potassium carbonate (414 mg, 3 mmol), potassium iodide (40mg) and 4-(chloromethyl)pyridine hydrochloride (250 mg, 1.5 mmol) in DMF(15 ml) was heated at 60° C. for 2 hours. The mixture was allowed tocool and partitioned between ethyl acetate and water. The organic layerwas separated, washed with water and brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was suspended in ethanol (20ml) and concentrated hydrochloric acid (0.5 ml) was added. The volatileswere removed by evaporation and the solid residue was azeotroped withtoluene. The solid product was recrystallised from isopropanol to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazolinehydrochloride (335 mg, 70%). ¹H NMR Spectrum: (DMSOd₆) 4.1(s, 3H);5.69(s, 2H); 7.46(dd, 1H); 7.52(s, 1H); 7.62(t, 1H); 7.69(dd, 1H);8.03(d, 2H); 8.55(s, 1H); 8.83(s, 1H); 8.93(d, 2H) MS-ESI: 411 [MH]⁺

Elemental Analysis: Found C 51.0 H 3.9 N 11.2 C₂₁H₁₆N₄O₂ClF 0.5H₂O1.95HCl Requires C 51.4 H 3.9 N 11.4%

EXAMPLE 46

Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (393 mg, 1.5 mmol) and2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (125 mg, 0.7 mmol)in methylene chloride (5 ml) and the mixture stirred for 2 hours atambient temperature. Methanol (10 drops) was added and the mixture waspoured on to a column of neutral aluminium oxide and the product wasseparated by elution with methylene chloride/acetonitrile/methanol(60/35/35). The purified solid product was triturated with ether andcollected by filtration. The solid was dissolved in methylenechloride/methanol and a solution of 3M ethereal hydrogen chloride (1 ml)was added. The solid was collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethoxy)-6-methoxyquinazoline(170 mg, 61%). m.p. 208-212° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD)2.52(s, 6H); 3.26(s, 3H); 3.98(s, 3H); 4.12(t, 2H); 4.46(t, 2H); 6.8(brs, 1H); 7.1(br s, 1H); 7.38(s, 1H); 7.46(dd, 1H); 7.62(t, 1H); 7.67(dd,1H); 8.18(s, 1H); 8.89(s, 1H) MS-ESI: 482 [MH]⁺

Elemental Analysis: Found C 52.2 H 5.2 N 12.2 C₂₅H₂₅N₅O₂ClF 1H₂O 2HClRequires C 52.4 H 5.1 N 12.2%

The starting material was prepared as follows:

A solution of 4-chloro-2,6-dimethylpyridine (849 mg, 6 mmol), (J. Het.Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3Methereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour.The reaction mixture was allowed to cool and was diluted with water. Theinsolubles were removed by filtration and the aqueous filtrate waspoured onto a suspension of magnesium sulphate (50 g) in ethyl acetate(100 ml). The insolubles were removed by filtration and the filtratedried (MgSO₄) and the solvent removed by evaporation. The solid residuewas triturated with ether, collected by filtration and dried undervacuum at 50° C. to give2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90%). m.p.139-144° C. ¹H NMR Spectrum: (CDCl₃) 2.4(s, 6H); 3.0(s, 3H); 3.51(t,2H); 3.81(t, 2H); 6.26(s, 2H) MS-ESI: 181 [MH]⁺

EXAMPLE 47

Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (393 mg, 1.5 mmol) and 2-(N-(4-pyridyl)amino)ethanol(97 mg, 0.7 mmol) in methylene chloride (8 ml) and the mixture stirredfor 2 hours at ambient temperature. The mixture was diluted with ethylacetate (5 ml), the solid product was collected by filtration andpurified by chromatography on an aluminium oxide column eluting withmethylene chloride/acetonitrile/methanol (60/35/5). The purified solidwas triturated with ether and collected by filtration. The solid wasdissolved in a mixture of methylene chloride/methanol and 3M etherealhydrogen chloride (0.5 ml) was added. The volatiles were removed byevaporation, the solid residue was suspended in ether, collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)quinazolinehydrochloride (95 mg, 37%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.87(t,2H); 4.00(s, 3H); 4.43(t, 2H); 6.97(dd, 1H); 7.15(dd, 1H); 7.43(s, 1H);7.46(dd, 1H); 7.66(t, 1H); 7.68(dd, 1H); 8.12(d, 1H); 8.21(s, 1H);8.34(d, 1H); 8.89(s, 1H) MS-ESI: 440 [MH]⁺

Elemental Analysis: Found C 50.0 H 4.3 N 13.2 C₂₂H₁₉N₅O₂ClF 0.8H₂O 2HClRequires C 50.0 H 4.3 N 13.2%

The starting material was prepared as follows:

Using a procedure analogous to that described for the starting materialin Example 46, 4-chloropyridine (3 g, 20 mmol) was treated withaminoethanol (6.1 g, 0.1 mol) to give 2-(N-(4-pyridyl))aminoethanol (400mg, 25%). m.p. 110-111° C. ¹H NMR Spectrum: (CDCl₃) 3.3(m, 2H); 3.81(m,2H); 4.94(br s, 1H); 6.44(d, 2H); 8.13(d, 2H) MS-ESI: 138 [MH]⁺

EXAMPLE 48

Using a procedure analogous to that described in Example 47,3-(N-methyl-N-(4-pyridyl)amino)propanol (116 mg, 0.7mmol) was treatedwith 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160mg, 0.5 mmol), (prepared as described for the starting material inExample 24), to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(N-methyl-N-(4-pyridyl)amino)propoxy)quinazolinehydrochloride (150 mg, 55%). m.p. 243-248° C. ¹H NMR Spectrum: (DMSOd₆;CD₃COOD) 2.2(t, 2H); 3.21(t, 3H); 3.82(t, 2H); 4.0(s, 3H); 4.31(t, 2H);6.95(br s, 1H); 7.2(br s, 1H); 7.39(s, 1H); 7.46(dd, 1H); 7.62(t, 1H);7.68(dd, 1H); 8.2(s, 1H); 8.3(br s, 2H); 8.87(s, 1H) MS-ESI: 468 [MH]⁺

Elemental Analysis: Found C 51.4 H 5.1 N 12.9 C₂₄H₂₃N₅O₂ClF 1.2H₂O1.95HCl Requires C 51.4 H 4.9 N 12.5%

The starting material was prepared as follows:

Using a procedure analogous to that described for the starting materialin Example 46, 4-chloropyridine (885 mg, 59 mmol) and3-(methylamino)propanol (2.1 g, 0.23 mmol), (Tetrahedron Lett. 1994, 35,1545-1548), were heated for 8 hours to give3-(N-methyl-N-(4-pyridyl)amino)propanol (979 mg, 61%). ¹H NMR Spectrum:(CDCl₃; CD₃COOD) 1.8-1.9(m, 2H); 3.16(s, 3H); 3.6-3.75(m, 4H) 6.8(br s,2H); 8.30(d, 2H) MS-ESI: 166 [MH]⁺

EXAMPLE 49

Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (393 mg, 1.5 mmol) and1-(2-hydroxyethyl)-2-methylimidazole (88 mg, 0.7 mmol), (Chem.Abs. 1964,60, 2949), in methylene chloride (8 ml) and the mixture stirred for 2hours at ambient temperature. The mixture was diluted with ether (8 ml)and the solid product was collected by filtration. The solid wasdissolved in methylene chloride/methanol and a solution of 3M etherealhydrogen chloride (0.5 ml)was added. The resulting precipitate wascollected by filtration, washed with ether and dried under vacuum togive4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)ethoxy)quinazolinehydrochloride (180 mg, 72%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.79(s,3H); 4.02(s, 3H); 4.59(t, 2H); 4.72(t, 2H); 7.40(s, 1H); 7.45(d, 1H);7.60(s, 1H); 7.62(t, 1H); 7.67(dd, 1H); 7.71(s, 1H); 8.23(s, 1H);8.89(s, 1H) MS-ESI: 428 [MH]⁺

Elemental Analysis: Found C 47.9 H 4.7 N 13.3 C₂₁H₁₉N₅O₂ClF 1.4H₂O2.1HCl Requires C 47.6 H 4.6 N 13.2%

EXAMPLE 50

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asolution of 1-(3-hydroxypropyl)imidazole (102 mg, 0.81 mmol), (EP0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(200 mg, 0.62 mmol), (prepared as described for the starting material inExample 24), and triphenylphosphine (492 mg, 1.8 mmol) in methylenechloride (4 ml) and the mixture stirred for 2 hours at ambienttemperature. The solvent was removed by evaporation and the residue waspurified by column chromatography eluting with methylenechloride/acetonitrile/methanol (60/35/5). The purified solid wasdissolved in methylene chloride/methanol and 5M ethereal hydrogenchloride (2 ml) was added. The volatiles were removed by evaporation,the solid residue was suspended in ether, collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-7-(3-(imidazol-1-yl)propoxy)-6-methoxyquinazolinehydrochloride (114 mg, 36%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.5(m,2H); 3.99(s, 3H); 4.32(t, 2H); 4.45(t, 2H); 7.39(s, 1H); 7.45(dd, 1H);7.61(t, 1H); 7.66(dd, 1H); 7.71(s, 1H); 7.84(s, 1H); 8.19(s, 1H);8.77(s, 1H); 9.20(s, 1H) MS-ESI: 428 [MH]⁺

Elemental Analysis: Found C 48.2 H 4.5 N 13.2 C₂₁H₁₉N₅O₂ClF 1.2H₂O1.9HCl Requires C 48.6 H 4.5 N 13.5%

EXAMPLE 51

7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (98mg, 0.23 mmol) was added to a solution of4-methyl-4H-1,2,4-triazole-3-thiol (40 mg, 0.34 mmol) andpotassium-t-butoxide (36 mg, 0.32 mmol) in DMF (1 ml) and the mixtureheated at 40° C. for 30 minutes. The reaction mixture was allowed tocool and was partitioned between ammonium chloride and ethyl acetate.The organic layer was separated, washed with water and brine, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography eluting with a gradient of methylenechloride/methanol (95/50 to 80/20). The purified solid product wastriturated with ether and collected by filtration. The solid wasdissolved in methylene chloride/methanol and 3M ethereal hydrogenchloride (0.5 ml) was added. The volatiles were removed by evaporationand the residue was crystallised from methylene chloride and ether. Thesolid was collected by filtration, washed with ether and dried undervacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-methyl-4H-1,2,4-triazol-3-ylthio)ethoxy)-quinazolinehydrochloride (90 mg, 79%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.78(s,3H); 3.81(t, 2H); 3.99(s, 3H); 4.57(t, 2H) 7.40(s, 1H); 7.46(dd, 1H);7.62(t, 1H); 7.67(dd, 1H); 8.16(s, 1H); 8.89(s, 1H); 9.68(s, 1H) MS-ESI:461 [MH]⁺

Elemental Analysis: Found C 43.7 H 3.9 N 14.9 C₂₀H₁₈N₆O₂ClFS 1H₂O 2HClRequires C 43.5 H 4.0 N 15.2%

The starting material was prepared as follows:

1,2-Dibromoethane (725 mg, 4 mmol) was added by portions of 70 μl every30 minutes to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1mmol), (prepared as described for the starting material in Example 24),and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml) heated at 35° C.The mixture was stirred for a further 30 minutes after the completion ofthe addition and then partitioned between ethyl acetate and water. Theorganic layer was separated, washed with water and brine, dried (MgSO₄)and the solvent removed by evaporation. The residue was triturated withpetroleum ether/ether, the solid was collected by filtration and driedunder vacuum to give7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200mg, 47%). ¹H NMR Spectrum: (DMSOd₆) 3.89(t, 2H); 3.96(s, 3H); 4.51(t,2H); 7.23(s, 1H); 7.35(dd, 1H); 7.55(dd, 1H); 7.59(t, 1H); 7.83(s, 1H);8.36(s, 1H); 9.57(s, 1H) MS-ESI: 428 [MH]⁺

EXAMPLE 52

Using an analogous procedure to that described in Example 51,7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (98mg, 0.23 mmol), (prepared as described for the starting material inExample 51), was treated with 5-mercapto-1-methyltetrazole (40 mg, 0.35mmol) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methyltetrazol-5-ylthio)ethoxy)-quinazolinehydrochloride (50 mg, 44%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.8(t,2H); 3.97(s, 6H); 4.57(t, 2H); 7.35(s, 1H); 7.46(dd, 1H); 7.62(t, 1H);7.70(dd, 1H); 8.12(s, 1H); 8.87(s, 1H) MS-ESI: 462 [MH]⁺

Elemental Analysis: Found C 45.1 H 3.7 N 19.3 C₁₉H₁₇N₇O₂ClFS 0.5H₂O 1HClRequires C 45.0 H 3.8 N 19.3%

EXAMPLE 53

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asolution of 2-methyl-1-(3-hydroxypropyl)imidazole (131 mg, 0.93 mmol),(EP 0060696 A1), triphenylphosphine (492 mg, 1.8 mmol) and4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.62 mmol), (prepared as described for the starting material in Example24), in methylene chloride (4 ml) and the mixture stirred for 2 hours atambient temperature. Further 2-methyl-1-(3-hydroxypropyl)imidazole (43mg, 0.31 mmol), triphenylphosphine (82 mg, 0.31 mmol) and diethylazodicarboxylate (50 μl, 0.31 mmol) were added and the mixture stirredfor a further 3 hours. The volatiles were removed by evaporation and theresidue was purified by column chromatography eluting with methylenechloride/methanol (93/7). The purified solid was dissolved in methylenechloride and 3M ethereal hydrogen chloride (2 ml) was added. Thevolatiles were removed by evaporation and the solid residue wassuspended in ether, collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)quinazolinehydrochloride (104 mg, 32%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.4(t,2H); 2.60(s, 3H); 4.0(s, 3H); 4.3-4.4(m, 4H); 7.41(s, 1H); 7.46(dd, 1H);7.58(s, 1H); 7.62(t, 1H); 7.67(dd, 1H); 7.70(s, 1H); 8.21(s, 1H);8.88(s, 1H) MS-ESI: 442 [MH]⁺

Elemental Analysis: Found C 49.8 H 5.0 N 12.5 C₂₂H₂₁N₅O₂ClF 1H₂O 2HClRequires C 50.1 H 5.0 N 12.7% 0.23 ether

EXAMPLE 54

A solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(methylaminoethoxy)quinazolinehydrochloride hydrate (135 mg, 0.3 mmol) and 2-chloropyrimidine (66 mg,0.6 mmol) in N,N-diisopropylethylamine (2 ml) was heated at reflux for 1hour. The mixture was allowed to cool and was triturated with ether. Thesolid product was collected by filtration and purified by columnchromatography eluting with methylene chloride/methanol (95/5). Thepurified oil was crystallised from ether and the solid collected byfiltration. The solid was dissolved in methylene chloride/methanol and asolution of 3M ethereal hydrogen chloride (0.5 ml) was added. Thesuspension was diluted with ether, the solid product collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyrimidin-2-yl)amino)ethoxy)quinazolinehydrochloride (52 mg, 33%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.36(s,3H); 3.9(s, 3H); 4.22(t, 2H); 4.51(t, 2H); 6.94(t, 1H); 7.36(s, 1H);7.46(d, 1H); 7.63(t, 1H); 7.66(dd, 1H); 8.08(s, 1H); 8.62(d, 2H); 8.9(s,1H) MS-ESI: 455 [MH]⁺

Elemental Analysis: Found C 49.8 H 4.4 N 15.9 C₂₂H₂₀N₆O₂ClF 1.1H₂O1.5HCl Requires C 49.9 H 4.5 N 15.9%

The starting material was prepared as follows:

A solution of di-t-butyl dicarbonate (4.52 g, 20 mmol) in THF (10 ml)was added to a solution of 2-(methylamino)ethanol (1.5 g, 20 mmol) inwater (10 ml) and THF (10 ml) and the mixture was stirred for 18 hoursat ambient temperature. The organic solvents was removed by evaporationand the residue was partitioned between water and ether. The organiclayer was separated, washed with 0.1 M hydrochloric acid and brine,dried (MgSO₄) and the solvent removed by evaporation to give2-(N-methyl-N-t-butoxycarbonylamino)ethanol (3 g, 85%) as an oil. ¹H NMRSpectrum: (CDCl₃) 1.46(s, 9H); 2.92(s, 3H); 3.39(t, 2H); 3.74(t, 2H)MS-ESI: 176 [MH]⁺

A solution of 2-(N-methyl-N-t-butoxycarbonylamino)ethanol (116 mg, 0.7mmol) in methylene chloride (1 ml) was added to a suspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),and triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (5 ml).Diethyl azodicarboxylate (261 mg, 1.5 mmol) was then added dropwise andthe mixture was stirred at ambient temperature for 4 hours. The reactionmixture was poured onto a column of silica and eluted with a gradient ofmethylene chloride/acetonitrile/methanol (70/30/0 to 70/20/10). Thepartially purified product was further purified by column chromatographyeluting with a gradient of methylene chloride/ether/methanol (60/40/0 to60/10/30). The pure oil was crystallised from ether, collected byfiltration and washed with ether to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-t-butoxycarbonylamino)ethoxy)quinazoline(450 mg, 63%). m.p. 194-196° C. ¹H NMR Spectrum: (CDCl₃) 1.46(s, 9H);3.05(br s, 3H); 3.72(br s, 2H); 4.02(s, 3H); 4.27(br s, 2H); 7.0(s, 1H);7.2-7.3(m, 3H); 8.54(t, 1H); 8.69(s, 1H) MS-ESI: 499 [MNa]⁺

Elemental Analysis: Found C 57.2 H 5.7 N 11.5 C₂₃H₂₆N₄O₄ClF 0.3H₂ORequires C 57.3 H 5.6 N 11.6%

TFA (4 ml) was added to a solution of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-t-butoxycarbonylamino)ethoxy)quinazoline(390 mg, 0.82 mmol) in methylene chloride (4 ml) and the mixture stirredfor 2 hours at ambient temperature. Toluene was added and the volatileswere removed by evaporation. The residue was dissolved in methylenechloride and 3M ethereal hydrogen chloride (1 ml) was added. Theresulting precipitate was collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(methylamino)ethoxy)quinazolinehydrochloride hydrate (290 mg; 79%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD)2.74(s, 3H); 3.53(t, 2H); 4.05(s, 3H); 4.53(t, 2H); 7.46(d, 1H); 7.47(s,1H); 7.6-7.7(m, 2H); 8.24(s, 1H); 8.91(s, 1H) MS-ESI: 377 [MH]⁺

Elemental Analysis: Found C 45.8 H 5.0 N 12.0 C₁₈H₁₈N₄O₂ClF 1.1H₂O 2HClRequires C 46.0 H 4.8 N 11.9%

EXAMPLE 55

Isonicotinoyl chloride (36 mg, 0.2 mmol) was added to a suspension of4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(methylamino)ethoxy)quinazolinehydrochloride hydrate (90 mg, 0.1 mmol), (prepared as described for thestarting material in Example 54), in methylene chloride (3 ml) andtriethylamine (80 mg, 0.8 mmol) was then added dropwise. The mixture wasstirred for 30 minutes at ambient temperature and the solvent was thenremoved by evaporation. The residue was partitioned between ethylacetate and water, the organic layer was separated, washed with brine,dried (MgSO₄) and the solvent removed by evaporation. The residue wasdissolved in methylene chloride/methanol and 3M ethereal hydrogenchloride (0.5 ml) was added. The suspension was diluted with ether, theprecipitate was collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridylcarbonyl)amino)ethoxy)quinazolinehydrochloride (75 mg, 67%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD; 95° C.)3.1(s, 3H); 3.8-3.9(br s, 2H); 4.1(s, 3H); 4.4-4.6(br s, 2H);7.4-7.45(m, 2H); 7.55(dd, 1H); 7.65(t, 1H); 7.9-8.0(br s, 2H); 8.28(s,1H); 8.8(s, 1H); 8.95(s, 2H) MS-ESI: 482 [MH]⁺

Elemental Analysis: Found C 51.7 H 4.6 N 12.0 C₂₄H₂₁N₅O₃ClF 1H₂O 1.7HClRequires C 51.5 H 4.6 N 12.3% 0.1 ether

EXAMPLE 56

A mixture of 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (100 mg, 0.4mmol), thionyl chloride (20 ml) and DMF (0.1 ml) was heated at refluxfor 1.5 hours. The volatiles were removed by evaporation and the residueazeotroped with toluene. A solution of 3-hydroxy-4-methylaniline (53 mg,0.04 mmol) in isopropanol (10 ml) was added to the solid residue and themixture was heated at reflux for 2 hours. The mixture was allowed tocool and the precipitated product collected by filtration, washed withisopropanol and dried to give4-(3-hydroxy-4-methylanilino)-7-(4-pyridylthio)quinazolinehydrochloride(103 mg, 73%). ¹H NMR Spectrum: (DMSOd₆) 2.17(s, 3H);7.05(dd, 1H); 7.17(d, 1H); 7.19(s, 1H); 7.64(d, 2H); 8.00(d, 1H);8.20(s, 1H); 8.66(d, 2H); 8.92(s, 1H); 9.05(d, 1H) MS-ESI: 361 [MH]⁺

Elemental analysis: Found C 53.2 H 4.6 N 11.8 C₂₀H₁₆N₄OS 1H₂O 2HClRequires C 53.2 H 4.4 N 12.4%

The starting material was prepared as follows:

A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide(30 ml) was heated at 150° C. for 6 hours. The reaction mixture waspoured onto ice/water 1/1 (250 ml). The precipitated solid was collectedby filtration, washed with water and dried to give7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).

Sodium hydride (3.3 g of a 50% suspension in mineral oil, 69 mmol) wasadded to a solution of 4-mercaptopyridine (8.12 g, 73 mmol) in DMF (100ml) and the mixture stirred for 30 minutes.7-Fluoro-3,4-dihydroquinazolin-4-one (1.5 g, 9 mmol) was added and thereaction heated at 100° C. for 4 hours. The mixture was allowed to cool,diluted with water and extracted with ethyl acetate. The organicextracts were washed with water and brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (97/3) to give7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (500 mg, 6%). ¹H NMRSpectrum: (DMSOd₆) 7.24(d, 2H); 7.54(dd, 1H); 7.70(d, 1H); 8.10(s, 1H);8.14(d, 1H); 8.44(d, 2H) MS-ESI: 256 [MH]⁺

EXAMPLE 57

A mixture of 4-chloro-2-fluoro-3-hydroxyaniline (118 mg, 0.7 mmol), (EP061741 A2), and 4-chloro-6-methoxy-7-((4-pyridyl)methoxy)quinazoline(200 mg, 0.7 mmol), (prepared as described for the starting material inExample 13), in isopropanol (10 ml) and ethereal hydrogen chloride (5ml) was heated at 80° C. for 2 hours and the mixture was allowed tocool. The precipitated product was collected by filtration, washed withisopropanol and dried to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazolinehydrochloride (110 mg, 31%). ¹H NMR Spectrum: (DMSOd₆) 3.96(s, 3H);5.38(s, 2H); 7.14(d, 1H); 7.24(s, 1H); 7.38(d, 1H); 7.48(d, 2H); 7.82(s,1H); 8.32(s, 1H); 8.58(d, 2H0; 9.48(s, 1H) MS-ESI: 427 [MH]⁺

EXAMPLE 58

A mixture of7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(150 mg, 0.47 mmol), phosphoryl chloride (0.2 ml) andN,N-dimethylaniline (0.2 ml) in toluene (5 ml) was heated at reflux for1 hour. The volatiles were removed by evaporation and the residue waspartitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The organic layer was separated, dried (MgSO₄) andthe solvent removed by evaporation. A solution of2-fluoro-5-hydroxy-4-methylaniline (67 mg, 0.47 mmol), (prepared asdescribed for the starting material in Example 13), in isopropanol (10ml) was added to the solid residue and the mixture was heated at refluxfor 2 hours. The mixture was allowed to cool and the precipitatedproduct collected by filtration, washed with acetone and dried to give7-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (70 mg, 30%). m.p. 245-250° C. ¹H NMR Spectrum: (DMSOd₆)2.30(s, 3H); 4.10(s, 3H); 5.45(s, 2H); 6.90(d, 1H); 7.10(d, 1H); 7.35(s,1H); 7.50(d, 1H); 7.65(s, 1H); 8.25(s, 1H); 8.45(d, 1H); 8.75(s, 1H);9.60(br s, 1H); 11.30(s, 1H) MS-ESI: 441 [MH]⁺

Elemental analysis: Found C 53.7 H 4.0 N 10.9 C₂₂H₁₈N₄O₃FCl 1H₂O 1HClRequires C 53.4 H 4.3 N 11.3%

The starting material was prepared as follows:

Oxalyl chloride (0.3 ml) was added to a mixture of4-(2-chloropyridine)carboxylic acid (950 mg, 6 mmol) and DMF (0.05 ml)in methylene chloride (20 ml) and the mixture stirred at ambienttemperature for 1 hour. The volatiles were removed by evaporation andethanol (10 ml) was added to the residue and the mixture stirred atambient temperature for 18 hours. Water was added and the mixture wasextracted with ethyl acetate (3×25 ml). The extracts were combined,dried (MgSO₄) and the solvent removed by evaporation to give ethyl4-(2-chloropyridine)carboxylate (700 mg, 63%) as a brown oil. ¹H NMRSpectrum: (DMSOd₆) 1.30(t, 3H); 4.37(q, 2H); 7.80(m, 2H); 8.60(d, 1H)

Lithium aluminium hydride (5 ml of a 1M solution in ether, 5 mmol) wasadded dropwise to a stirred solution of ethyl4-(2-chloropyridine)carboxylate (700 mg, 3.8 mmol) in ether (10 ml) at0° C. The mixture was allowed to warm to ambient temperature, wet etherand 2M sodium hydroxide solution (2 ml). The insolubles were removed byfiltration, the organic phase was separated and the aqueous layer wasextracted with ether (3×25 ml). The extracts were combined, dried(MgSO₄) and the solvent removed by evaporation to give2-chloro-4-hydroxymethylpyridine (180 mg, 33%) as a brown oil whichcrystallised on standing. ¹H NMR Spectrum: (DMSOd₆) 4.55(s, 2H); 5.50(brs, 1H); 7.32(d, 1H); 7.20(s, 1H); 8.30(d, 1H)

A mixture of 2-chloro-4-hydroxymethylpyridine (180 mg, 1.25 mmol),thionyl chloride (Q02 ml) in toluene (10 ml) was stirred at ambienttemperature for 1 hour. The volatiles were removed by evaporation togive 2-chloro-4-chloromethylpyridine hydrochloride (180 mg, 0.9 mmol). Amixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (268 mg, 1 mmol),(prepared as described for the starting material in Example 13),potassium carbonate (680 mg, 5 mmol) and DMF (10 ml) was added to thiscrude product and the mixture was heated at 90° C. for 1 hour. Themixture was allowed to cool, diluted with water and extracted with ethylacetate (3×70 ml). The extracts were combined, washed with water (×3)and brine, dried (MgSO₄) and the solvent removed by evaporation to give7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (260 mg,66%) as a solid. ¹H NMR Spectrum: (DMSOd₆) 4.00(s, 3H); 5.45(s, 2H);7.30(m, 3H); 7.42(s, 1H); 7.4-7.5(m, 3H); 7.60(s, 1H); 7.62(s, 1H);8.44(d, 1H); 8.52(s, 1H) MS-ESI: 394 [MH]⁺

A mixture of7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (260 mg,0.7 mmol) and 2M hydrochloric acid (15 ml) was heated at 85° C. for 2hours. The mixture was allowed to cool and adjusted to pH6-7 with sodiumhydrogen carbonate solution. The resulting precipitate was collected byfiltration and dried to give7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(160 mg, 76%). ¹H NMR Spectrum: (DMSOd₆) 3.90(s, 3H); 5.36(s, 2H);7.18(s, 1H); 7.45(m, 2H); 7.46(s, 1H); 7.59(s, 1H); 8.42(d, 1H) MS-ESI:318 [MH]⁺

EXAMPLE 59

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(950 mg, 3 mmol), (prepared as described for the starting material inExample 24), 2-bromo-4-bromomethylpyridine (765 mg, 3 mmol) andpotassium carbonate (2.38 g 17 mmol) in DMF (10 ml) was heated at 80° C.for 2 hours. The mixture was allowed to cool, poured into water andextracted with ethyl acetate. The combined extracts were dried (MgSO₄)and the solvent removed by evaporation and azeotroped with toluene. Theresidue was triturated with ethyl acetate/hexane and the solid productcollected by filtration, washed with ethyl acetate/hexane and dried togive7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline(647 mg, 44%). m.p. 210-212° C. ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H);5.40(s, 2H); 7.25(s, 1H); 7.30(d, 1H); 7.50(s, 1H); 7.50(d, 1H); 7.55(m,2H); 7.74(s, 1H); 7.86(s, 1H); 8.35(br s, 1H); 8.42(d, 1H); 9.56(s, 1H)MS-ESI: 489 [MH]³⁰

Elemental analysis: Found C 52.0 H 3.2 N 11.2 C₂₁H₁₅N₄O₂BrClF Requires C51.5 H 3.1 N 11.4%

The starting material was prepared as follows:

A mixture of 2-bromo-4-methylpyridine (12.2 g), N-bromosuccinimide (30g) and 2,2′-azobis(2-methylpropionitrile) (100 mg) in carbontetrachloride (200 ml) was heated at reflux for 2.5 hours. The mixturewas allowed to cool and the insoluble material removed by filtration.The solvent was removed from the filtrate by evaporation and the residuewas purified by filtration through a silica pad eluting with ethylacetate/hexane (10/1) to give 2-bromo-4-bromomethylpyridine. ¹H NMRSpectrum: (DMSOd₆) 4.65(s, 2H); 7.50(d, 1H); 7.42(s, 1H); 7.70(s, 1H);8.35(d, 1H) MS-ESI: 250 [MH]⁺

EXAMPLE 60

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(600 mg, 2 mmol), (prepared as described for the starting material inExample 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 3mmol) and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) was heated at80° C. for 30 minutes. The mixture was allowed to cool, poured intowater and extracted with ethyl acetate. The combined extracts were dried(MgSO₄) and the solvent removed by evaporation and azeotroped withtoluene. The residue was triturated with ethyl acetate/hexane, the solidproduct collected by filtration and purified by column chromatographyeluting with ethyl acetate and further chromatography eluting withmethylene chloride/methanol (99/1). The purified product wasrecrystallised from ethyl acetate/hexane to give4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline(35 mg, 4%). m.p. 209-213° C. ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H);5.44(s, 2H); 7.26(s, 1H); 7.34(dd, 1H); 7.53(dd, 1H); 7.58(d, 1H);7.80(d, 1H); 7.85(s, 1H); 8.27(s, 1H); 8.35(s, 1H); 8.80(d, 1H); 9.60(s,1H) MS-ESI: 436 [MH]⁺

Elemental analysis: Found C 60.3 H 3.4 N 16.1 C₂₂H₁₅N₅O₂ClF Requires C60.6 H 3.5 N 16.1%

The starting material was prepared as follows:

Tetrabutyl ammonium fluoride (9 ml of a 1M solution in THF, 9 mmol) wasadded to a solution of 2-cyano-4-dimethyl-t-butylsilyloxymethylpyridine(1.4 g, 5.6 mmol), (J.Het. Chem. 1993, 30, 631), in THF (15 ml) and themixture was stirred for 2 hours at ambient temperature. Water was addedand the volatiles were removed by evaporation. The residue waspartitioned between ethyl acetate and water. The organic layer wasseparated and the aqueous layer extracted with ethyl acetate. Thecombined extracts were dried (MgSO₄) and the solvent removed byevaporation to give 2-cyano-4-hydroxymethylpyridine (0.55 g, 73%). ¹HNMR Spectrum: (DMSOd₆) 4.65(s, 2H); 5.70(t, 1H); 7.70(d, 1H); 7.95(s,1H); 8.75(d, 1H)

A mixture of 2-cyano-4-hydroxymethylpyridine (0.51 g, 3.8 mmol)andthionyl chloride (0.6 ml) in toluene (20 ml) was stirred at roomtemperature for 1 hour. The volatiles were removed by evaporation andthe residue azeotroped with toluene to give4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 86%). ¹H NMRSpectrum: (DMSOd₆) 4.75(s, 2H); 7.75(dd, 1H); 8.05(s, 1H); 8.34(d, 1H)

EXAMPLE 61

A mixture of7-((6-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(190 mg, 0.4 mmol), thionyl chloride (5 ml) and DMF (0.1 ml) was heatedat reflux for 2 hours. The volatiles were removed by evaporation and theresidue azeotroped with toluene. A solution of 4-chloro-2-fluoroaniline(1 ml) in isopropanol (15 ml) was added to the solid residue and themixture was heated at reflux for 3 hours. The mixture was allowed tocool and the precipitated product collected by filtration, washed withisopropanol and dried to give4-(4-chloro-2-fluoroanilino)-7-((6-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxyquinazolinehydrochloride (110 mg, 41%). m.p. 271-273° C. (decomp.) ¹H NMR Spectrum:(DMSOd₆) 4.08(s, 3H); 5.35(s, 2H); 6.70(s, 1H); 7.00(s, 1H); 7.30(s,1H); 7.40(d, 1H); 7.60(m, 2H); 8.30(s, 1H); 8.75(s, 1H) MS-ESI: 461[MH]⁺

The starting material was prepared as follows:

A mixture of 2,6-dichloro-4-hydroxymethylpyridine (1.72 g, 16 mmol) and40% aqueous sodium hydroxide solution (5 ml) in methanol (50 ml) washeated at reflux for 24 hours. The mixture was allowed to cool and thevolatiles removed by evaporation. The residue was extracted with ethylacetate and the solvent removed from the extracts by evaporation. Theresidue was recrystallised from ethyl acetate/hexane to give2-chloro-4-hydroxymethyl-6-methoxypyridine (490 mg, 28%). ¹H NMRSpectrum: (DMSOd₆) 3.80(s, 3H); 4.45(d, 2H); 5.45(t, 1H); 6.70(s, 1H);6.98(s, 1H)

Thionyl chloride (1.0 ml) was added to a solution of2-chloro-4-hydroxymethyl-6-methoxypyridine (0.9 g, 5.2 mmol) in toluene10 ml) and the mixture stirred at ambient temperature for 1 hour. Thevolatiles were removed by evaporation, the residue was azeotroped withtoluene and dried under vacuum to give2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 74%).¹H NMR Spectrum: (DMSOd₆) 3.85(s, 3H); 4.70(s, 2H); 6.90(s, 1H); 7.15(s,1H)

A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol),(prepared as described for the starting material in Example 13),2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 3.9mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heatedat 80° C. for 1 hour. The mixture was allowed to cool, diluted withwater and the precipitated product collected by filtration, washed withwater and dried to give7-((2chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline(1.38 g, 79%). ¹H NMR Spectrum: (CDCl₃) 3.95(s, 3H); 4.04(s, 3H);5.20(s, 2H); 6.70(s, 1H); 6.95(s, 1H) 7.18(m, 3H); 7.30(t, 1H); 7.40(t,2H); 7.58(s, 1H); 8.52(s, 1H) MS-ESI: 424 [MH]⁺

A mixture of7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline(400 mg, 0.95 mmol) and 2M hydrochloric acid (20 ml ) was heated atreflux for 3 hours. The mixture was allowed to cool and adjusted topH6-7 with aqueous ammonia solution. The resulting precipitate wascollected by filtration washed with water and dried to give crude7-((6-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(190 mg, 60%).

EXAMPLE 62

Thionyl chloride (0.6 ml) was added to a solution of4-hydroxymethyl-2-methoxypyridine (0.59 g, 4.2 mmol) in toluene (10 ml)and the mixture stirred at ambient temperature for 1.5 hours. Thevolatiles were removed by evaporation and the residue was azeotropedwith toluene and dried under vacuum to give crude4-chloromethyl-2-methoxypyridine hydrochloride (0.50 g, 2.6 mmol) whichwas used directly. This product was then added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (420 mg, 1.3mmol), (prepared as described for the starting material in Example 24),and potassium carbonate (10 g 7 mmol) in DMF (8 ml) and the resultingmixture was heated at 75° C. for 2 hours. The mixture was allowed tocool, diluted with water and the precipitated solid collected byfiltration, washed with water and dried to give4-(4-chloro-2-fluoroanilino)-7-((2-methoxy-4-pyridyl)methoxy)-6-methoxyquinazoline(140 mg, 25%). m.p. 202-204° C. ¹H NMR Spectrum: (DMSOd₆) 3.85(s, 3H);3.98(s, 3H); 5.35(s, 2H); 6.88(s, 1H); 7.05(d, 1H); 7.24(s, 1H);7.35(dd, 1H); 7.54(dd, 1H); 7.58(t, 1H); 7.84(s, 1H); 8.11(d, 1H);8.35(s, 1H); 9.58(br s, 1H) MS -ESI: 441 [MH]⁺

Elemental analysis: Found C 59.9 H 4.1 N 12.4 C₂₂H₁₈N₄O₃ClF Requires C59.9 H 4.1 N 12.7%

The starting material was prepared as follows:

A mixture of ethyl 2-hydroxy-pyridine-4-carboxylate (1.0 g, 6 mmol),(Chem. Abs. 1957, 8740c), methyl iodide (1 ml) and silver(I)carbonate(1.64 g) in toluene (20 ml) was heated at reflux for 2 hours. Themixture was allowed to cool and the insolubles removed by filtrationthrough diatomaceous earth and the pad was washed through with ethylacetate. The filtrate was washed with water, dried (MgSO₄) and thesolvent removed by evaporation to give ethyl2-methoxy-pyridine-4-carboxylate (0.93 g, 86%) as a yellow oil. ¹H NMRSpectrum: (CDCl₃) 1.30(t, 3H); 3.90(s, 3H); 4.30(q, 2H); 7.24(s, 1H);7.35(d, 1H); 8.20(d, 1H) MS-ESI: 182 [MH]⁺

A solution of ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 5 mmol) inether (5 ml) was added to lithium aluminium hydride (0.3 g, 8 mmol) inether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Waterwas added, the mixture was filtered through diatomaceous earth and thepad was washed through with ethyl acetate. The filtrate was extractedwith ethyl acetate and the combined extracts were washed with brine,dried (MgSO₄) and the solvent removed by evaporation to give4-hydroxymethyl-2-methoxypyridine (0.64 g, 89%) as a yellow oil. ¹H NMRSpectrum: (CDCl₃) 3.86(s, 3H); 4.62(s, 2H); 6.65(s, 1H); 6.76(d, 1H);8.05(d, 1H) MS-ESI: 140 [MH]⁺

EXAMPLE 63

Thionyl chloride (0.3 ml) was added to a solution of4-hydroxymethyl-2-methylpyridine (240 mg, 1.9 mmol) in toluene (10 ml)and the mixture stirred at ambient temperature for 2 hours. Thevolatiles were removed by evaporation, the residue azeotroped withtoluene and dried under vacuum to give crude4-chloromethyl-2-methylpyridine hydrochloride which was used directly.This product was then added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (510 mg, 1.6mmol), (prepared as described for the starting material in Example 24),and potassium carbonate (1.4 g 10 mmol) in DMF (8 ml) for 90 hours. Themixture was diluted with water and the precipitated solid collected byfiltration, washed with water and dried to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)quinazoline(290 mg, 43%), a sample was recrystallised from ethyl acetate/hexane.m.p. 221-224° C. ¹H NMR Spectrum: (CDCl₃)2.50(s, 3H); 4.00(s, 3H);5.20(s, 2H); 6.98(s, 1H); 7.15(d, 1H); 7.2(m, 4H); 8.45(m, 2H); 8.60(s,1H)

Elemental analysis: Found C 61.7 H 4.2 N 13.2 C₂₂H₁₈N₄O₂ClF Requires C62.2 H 4.3 N 13.2%

The starting material was prepared as follows:

Oxalyl chloride (1.9 g, 15 mmol) was added to2-chloro-6-methyl-pyridine-4-carboxylic acid (1.7 g, 10 mmol) inmethylene chloride (30 ml) and the mixture stirred for 2 hours. Thevolatiles were removed by evaporation and methanol (20 ml) added to theresidue. The mixture was stirred for 1 hour and the volatiles removed byevaporation to give methyl 2-chloro-6-methyl-pyridine-4-carboxylate(1.85 g, 100%) as an off-white solid. ¹H NMR Spectrum: (CDCl₃)2.55(s,3H); 3.90(s, 3H); 7.55(s, 1H); 7.60(s, 1H); MS-ESI: 186 [MH]⁺

A mixture of methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.8 g, 10mmol) and 10% palladium-on-charcoal catalyst (200 mg) in methanol (100ml) was stirred under hydrogen at 5 atmospheres pressure. The catalystwas removed by filtration and the volatiles removed from the filtrate byevaporation. The residue was treated with 10% aqueous sodium hydroxidesolution and extracted with ether (3×30 ml). The combined extracts weredried (MgSO₄) and the solvent removed by evaporation to give methyl2-methyl-pyridine-4-carboxylate (800 mg, 53%) as an oil.

A solution of methyl 2-methyl-pyridine-4-carboxylate (800 mg, 6 mmol) inether (5 ml) was added to lithium aluminium hydride (340 mg, 9 mmol) inether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Waterwas added, the mixture was filtered through diatomaceous earth and thepad was washed through with ethyl acetate. The filtrate was extractedwith ethyl acetate and the combined extracts were washed with brine,dried (MgSO₄) and the solvent removed by evaporation to give4-hydroxymethyl-2-methylpyridine (240 mg, 38%) as a yellow oil. ¹H NMRSpectrum: (CDCl₃)2.48(s, 3H); 5.44(s, 2H); 7.00(d, 1H); 7.10(s, 1H);8.40(d, 1H) MS-ESI: 124 [MH]⁺

EXAMPLE 64

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(350 mg, 0.9 mmol), (prepared as described for the starting material inExample 24), 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (203mg, 0.95 mmol) and potassium carbonate (303 mg 2.2 mmol) in NMP (20 ml)was heated at 90° C. for 2 hours. The mixture was allowed to cool,diluted with water and extracted with ethyl acetate. The combinedextracts were washed with water, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol (100/0 increasing to 90/10) togive4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline(75 mg, 17%) as a solid. ¹H NMR Spectrum: (DMSOd₆) 3.46(s, 3H); 3.93(s,3H); 4.39-4.44(m, 4H); 7.13(dd, 2H); 7.23(s, 1H); 7.31(dd, 1H);7.49-7.60(m, 2H); 7.79(s, 1H); 8.37(s, 1H); 9.51(s, 1H) MS-ESI: 460[MH]⁺

Elemental analysis: Found C 52.8 H 4.0 N 14.3 C₂₁H₁₉N₅O₂ClFS 1 H₂ORequires C 52.8 H 4.4 N 14.7%

The starting material was prepared as follows:

2-Chloroethanol (3 g, 37 mmol) was added to a solution of2-mercapto-1-methylimidazole (3.45 g, 30 mmol) in 2M aqueous sodiumhydroxide solution (30 ml) and the mixture heated at 100° C. for 2hours. The mixture was allowed to cool and extracted with ethyl acetate.The combined extracts were dried (MgSO₄) and the solvent removed byevaporation to give 2-(2-hydroxyethylthio)-1-methylimidazole (3.9 g,82%). ¹H NMR Spectrum: (DMSOd₆) 3.04(t, 2H); 3.30(s, 3H); 3.54(t, 2H);5.00(s, 1H); 6.87(s, 1H); 7.20(s, 1H)

Thionyl chloride (1.41 ml, 19 mmol) was slowly added to a solution of2-(2-hydroxyethylthio)-1-methylimidazole (1.81 g, 11 mmol) intrichloromethane (20 ml) at 5° C. The mixture was stirred for 1 hour at5° C. and then for 3 hours at ambient temperature. The volatiles wereremoved by evaporation and the residue azeotroped with toluene to give2-(2-chloroethylthio)-1-methylimidazole hydrochloride (1.5 g, 77%). ¹HNMR Spectrum: (DMSOd₆) 3.58 (t, 2H); 3.78(s, 3H); 3.80(t, 2H); 7.78(d,1H); 7.83(d, 1H)

EXAMPLE 65

Thionyl chloride (0.55 ml, 7.5 mmol) was added to a solution of1-(3-hydroxypropyl)-1,2dihydro-2- pyridone (770 mg, 5 mmol) intrichloromethane (15 ml) at 5° C. The mixture was stirred at 5° C. for 1hour and then at ambient temperature for 2 hours. The volatiles wereremoved by evaporation, the residue azeotroped with toluene and driedunder vacuum to give crude 1-(3-chloropropyl)-1,2-dihydro-2-pyridone(500 mg) which was used directly. Part of this product (206 mg, 1.2mmol) was then added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0mmol), (prepared as described for the starting material in Example 24),and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) and thereaction mixture was heated at 90° C. for 2 hours. The mixture wasallowed to cool, diluted with water and extracted with ethyl acetate.The combined extracts were wash ed with water, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol mixtures (100/0increasing to 95/5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline(194 mg, 50%). m.p. 216-218° C. ¹H NMR Spectrum: (DMSOd₆) 2.18(m, 2H);3.90(s, 3H); 4.06(t, 2H); 4.15(t, 2H); 6.18(t, 1H); 6.38(d, 1H); 7.15(s,1H); 7.30-7.42(m, 2H); 7.50-7.64(m, 3H); 7.79(s, 1H); 8.34(s, 1H);9.50(s, 1H) MS-ESI: 455 [MH]⁺

Elemental analysis: Found C 59.4 H 4.6 N 12.1 C₂₃H₂₀N₄O₃ClF 0.5 H₂ORequires C 59.6 H 4.6 N 12.1%

The starting material was prepared as follows:

Sodium hydride (1.31 g of a 50% suspension in mineral oil, 27 mmol) wasadded to a solution of 2-hydroxypyridine (2.35 g, 24 mmol) in DMF (50ml) and the mixture stirred for 30 minutes.2-(3-Bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol), (J. Chem. Soc.1963, 3440), was added and the mixture heated at 100° C. for 3 hours andthen stirred at ambient temperature for 18 hours. The reaction mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with water, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol mixtures (100/0 increasing to97/3) to give:1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.6 g;30%). ¹H NMR Spectrum: (DMSOd₆) 1.39-1.75(m, 6H); 1.85(m, 2H);3.24-3.42(m, 3H); 3.58-3.74(m, 2H); 3.90(t, 2H); 4.52(s, 1H); 6.18(t,1H); 6.35(d, 1H); 7.38(dd, 1H); 7.60(dd, 1H) MS-ESI: 238 [MH]⁺ and2-(3-(2-tetrahydropyranyloxy)propyloxy)pyridine (1.43 g, 27%). ¹H NMRSpectrum: (DMSOd₆) 1.38-1.70(m, 6H); 1.90(m, 2H); 3.30(m, 3H);3.34-3.50(m, 2H); 3.62-3.80(m, 2H); 4.30(t, 2H); 4.52(s, 1H); 6.78(d,1H); 6.92(dd, 1H); 7.64(m, 1H); 8.15(dd, 1H) MS-ESI: 238 [MH]⁺

A solution of1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.0 g, 4.5mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at50° C. for 4 hours. The volatiles were removed by evaporation and theresidue azeotroped with toluene to give1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (680 mg, 99%) as an off-whitesolid. ¹H NMR Spectrum: (DMSOd₆) 1.74(m, 2H); 3.38(m, 2H); 3.90(t, 2H);4.58(s, 1H); 6.18(dd, 1H); 6.38(d, 1H); 7.38(m, 1H); 7.60(dd, 1H)

EXAMPLE 66

Thionyl chloride (0.80 ml, 11 mmol) was added to a solution of2-(3-hydroxypropylthio)-1-methylimidazole (1.25 g, 7.3 mmol) intrichloromethane (25 ml) at 5° C. The mixture was stirred at 5° C. for 1hour and then at ambient temperature for 2 hours. The volatiles wereremoved by evaporation, the residue azeotroped with toluene and driedunder vacuum to give crude 2-(3-chloropropylthio)-1-methylimidazolehydrochloride (1.0 g) which was used directly. Part of this product (226mg, 1.0 mmol) was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0mmol), (prepared as described for the starting material in Example 24),and potassium carbonate.(303 mg 2.2 mmol) in NMP (20 ml) and the mixturewas heated at 90° C. for 2 hours. The mixture was allowed to cool,diluted with water and extracted with ethyl acetate. The combinedextracts were washed with water, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol (100/0 increasing to 95/5) togive4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline(29 mg, 6%). m.p. 199-201° C. ¹H NMR Spectrum: (DMSOd₆) 2.22(m, 2H);3.44(s, 3H); 3.94(s, 3H); 4.10(m, 4H); 7.10(d, 2H); 7.30(dd, 1H);7.50-7.60(m, 2H); 7.79(s, 1H); 8.34(s, 1H); 9.50(s, 1H) MS-ESI: 474[MH]⁺

Elemental analysis: Found C 50.9 H 4.8 N 13.2 C₂₂H₂₁N₅O₂ClFS 2.5 H₂ORequires C 50.9 H 5.1 N 13.5%

The starting material was prepared as follows:

Sodium hydride (0.95 g of a 50% suspension in mineral oil, 20 mmol) wasadded to a solution of 2-mercapto-1-methylimidazole (2.26 g, 19 mmol) inDMF (100 ml) and the mixture stirred for 30 minutes.2-(3-Bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol), (J. Chem. Soc.1963, 3440), was added and the mixture heated at 100° C. for 3 hours andthen stirred at ambient temperature for 18 hours. The reaction mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with water, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol mixtures (100/0 increasing to97/3) to give 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole(2.5 g, 55%). ¹H NMR Spectrum: (DMSOd₆) 1.38-1.72(m, 6H); 1.80(m, 2H);3.0(t, 2H); 3.36-343(m, 2H); 3.58(s, 3H); 3.62-3.78(m, 2H); 4.50(s, 1H);6.90(s, 1H); 7.21(s, 1H)

A solution of 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole(2.0 g, 7.8 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) washeated at 50° C. for 4 hours. The volatiles were removed by evaporationand the residue azeotroped with toluene to give2-(3-hydroxypropylthio)-1-methylimidazole (1.3 g, 100%) as an off-whitesolid. ¹H NMR Spectrum: (DMSOd₆) 1.68(m, 2H); 2.98(t, 2H); 3.42(t, 2H);3.57(s, 3H); 4.10(s, 1H); 6.90(d, 1H); 7.20(d, 1H)

EXAMPLE 67

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(350 mg, 1.0 mmol), (prepared as described for the starting material inExample 24), 4-(3-chloropropoxy)pyridine hydrochloride (206 mg, 1.0mmol) and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) washeated at 90° C. for 2 hours. The mixture was allowed to cool, dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with water, dried (MgSO₄) and the solvent removed by evaporation.The residue was purified by column chromatography eluting with methylenechloride/methanol mixtures (100/0 increasing to 95/5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline(257 mg, 56%). m.p. 138-140° C. ¹H NMR Spectrum: (DMSOd₆) 2.25(m, 2H);3.92(s, 3H); 4.24(t, 2H); 4.30(t, 2H); 6.98(dd, 2H); 7.20(s, 1H);7.31(dd, 1H); 7.55(dd, 2H); 7.79(s, 1H); 8.32-8.38(m, 3H); 9.50(s, 1H)MS-ESI: 455 [MH]⁺

Elemental analysis: Found C 58.4 H 4.7 N 11.8 C₂₃H₂₀N₄O₃ClF 1 H₂ORequires C 58.4 H 4.7 N 11.8%

The starting material was prepared as follows:

A mixture of 4-chloropyridine (7 g, 47 mmol), ethylene glycol (17.9 g,235 mmol) and sodium hydroxide (4.67 g, 195 mmol) in DMSO (80 ml) washeated at 100° C. for 24 hours. Most of the solvent was removed byevaporation and the residue was diluted with ice water. The aqueousmixture was extracted with ethyl acetate, the extracts combined, dried(MgSO₄) and the solvent removed by evaporation. The residue was purifiedby column chromatography eluting with methylene chloride/methanolmixtures (100/0 increasing to 97/3) to give 4-(3-hydroxypropoxy)pyridine(3.2 g, 45%).

Thionyl chloride (2.2 ml, 30 mmol) was added slowly to a solution of4-(3-hydroxypropoxy)pyridine (3.1 g, 20 mmol) in trichloromethane (40ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then atambient temperature for 2 hours. The volatiles were removed byevaporation, the residue azeotroped with toluene and dried under vacuumto give 4-(3-chloropropoxy)pyridine hydrochloride (3.81 g, 91%) as asolid. ¹H NMR Spectrum: (DMSOd₆) 2.22(m, 2H); 3.80(t, 2H); 4.42(t, 2H);7.55(d, 2H); 8.72(d, 2H) MS-ESI: 172 [MH]⁺

EXAMPLE 68

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(350 mg, 1.0 mmol), (prepared as described for the starting material inExample 24), 4-(2-chloroethylthio)pyridine hydrochloride (252 mg, 1.2mmol) and potassium carbonate (454 mg, 3.3 mmol) in NMP (30 ml) washeated at 90° C. for 2 hours. The mixture was allowed to cool, dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with water, dried (MgSO₄) and the solvent removed by evaporation.The residue was purified by column chromatography eluting with ethylacetate/methanol mixtures (100/0 increasing to 75/25) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline(13 mg, 3%). m.p. 182-186° C. ¹H NMR Spectrum: (DMSOd₆) 3.58(t, 2H);3.90(s, 3H); 4.40(t, 2H); 7.20(s, 1H); 7.32(d, 1H); 7.40(d, 2H);7.50-7.60(m, 2H); 7.80(s, 1H); 8.32(s, 1H); 8.38(d, 2H); 9.57(s, 1H)MS-ESI: 457 [MH]⁺

The starting material was prepared as follows:

Sodium hydride (890 mg of a 50% suspension in mineral oil, 19 mmol) wasadded to a solution of 4-mercaptopyridine (2.34 g, 21 mmol) in DMF (75ml) and the mixture stirred for 30 minutes.2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc.1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hoursand then stirred at ambient temperature for 18 hours. The reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with water, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol mixtures (100/0increasing to 97/3) to give4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.8 g, 56%). ¹H NMRSpectrum: (DMSOd₆) 1.35-1.64(m, 6H); 3.35-3.42(m, 1H); 3.58-3.82(m, 3H);4.60(s, 1H); 7.30(dd, 2H); 8.33(dd, 2H)

A solution of 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.73 g,11 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heatedat 50° C. for 4 hours. The volatiles were removed by evaporation and theresidue azeotroped with toluene to give 4-(2-hydroxyethylthio)pyridine(1.39 g, 79%) as an off-white solid. ¹H NMR Spectrum: (DMSOd₆) 3.10(t,2H); 3.60(q, 2H); 5.00(t, 1H); 7.22(d, 2H); 8.30(d, 2H)

Thionyl chloride (0.98 ml, 13.5 mmol) was added slowly to a solution of4-(2-hydroxyethylthio)pyridine (1.39 g, 9.0 mmol) in trichloromethane(25 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then atambient temperature for 2 hours. The volatiles were removed byevaporation, the residue azeotroped with toluene and dried under vacuumto give 4-(2-chloroethylthio)pyridine hydrochloride (500 mg, 26%) as asolid. ¹H NMR Spectrum: (DMSOd₆) 3.65(t, 2H); 3.90(t, 2H); 7.90(d, 2H);8.60(d, 2H) MS-ESI: 174 [MH]⁺

EXAMPLE 69

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(350 mg, 1.0 mmol), (prepared as described for the starting material inExample 24), 3-(2-chloroethoxy)pyridine hydrochloride (234 mg, 1.2 mmol)and potassium carbonate (456 mg, 3.3 mmol) in NMP (20 ml) was heated at90° C. for 2 hours. The mixture was allowed to cool, diluted with waterand extracted with ethyl acetate. The combined extracts were washed withwater, dried (MgSO₄) and the solvent removed by evaporation. The residuewas purified by column chromatography eluting with methylenechloride/methanol mixtures (100/0 increasing to 95/5) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline(95 mg, 20%). m.p. 188-190° C. ¹H NMR Spectrum: (DMSOd₆) 3.90(s, 3H);4.45(m, 4H); 7.24(s, 1H); 7.18(dd, 1H); 7.2-7.60(m, 3H); 7.80(s, 1H);8.20(d, 1H); 8.35(s, 2H); 9.50(s, 1H) MS-ESI: 441 [MH]⁺

Elemental analysis: Found C 55.0 H 3.9 N 11.8 C₂₂H₁₈N₄O₃ClF 2 H₂ORequires C 55.4 H 4.6 N 11.7%

The starting material was prepared as follows:

Sodium hydride (1.02 g of a 50% suspension in mineral oil, 42 mmol) wasadded to a solution of 3-hydroxypyridine (2.01 g, 21 mmol) in DMF (50ml) and the mixture stirred for 30 minutes.2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc.1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hoursand then stirred at ambient temperature for 18 hours. The reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with water, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol mixtures (100/0increasing to 97/3) to give3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (2.28 g, 48%). ¹H NMRSpectrum: (DMSOd₆) 1.38-1.65(m, 6H); 3.40(m, 1H); 3.65-3.79(m, 2H);3.85-3.95(m, 1H); 4.20(t, 2H); 4.62(s, 1H); 7.30(dd, 1H); 7.39(dd, 1H);8.15(d, 1H); 8.28(d, 1H) MS-ESI: 224 [MH]⁺

A solution of 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (1.54 g, 7mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at50° C. for 4 hours. The volatiles were removed by evaporation and theresidue azeotroped with toluene to give 3-(2-hydroxyethoxy)pyridine (820mg, 86%) as an off-white solid. ¹H NMR Spectrum: (DMSOd₆) 3.70(t, 2H);4.05(t, 2H); 4.85(s, 1H); 7.25(dd, 1H); 7.37(dd, 1H); 8.10(d, 1H);8.24(d, 1H) MS-ESI: 140 [MH]⁺

Thionyl chloride (0.89 ml, 12 mmol) was added slowly to a solution of3-(2-hydroxyethoxy)pyridine (1.13 g, 8 mmol) in trichloromethane (20 ml)at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambienttemperature for 2 hours. The volatiles were removed by evaporation, theresidue azeotroped with toluene and dried under vacuum to give3-(2-chloroethoxy)pyridine hydrochloride (300 mg, 19%) as a solid. ¹HNMR Spectrum: (DMSOd₆) 3.99(t, 2H); 4.42(t, 2H); 7.82(dd, 1H); 8.05(dd,1H); 8.42(d, 1H); 8.62(s, 1H)

EXAMPLE 70

2-Fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol), (prepared asdescribed for the starting material in Example 13), was added to asolution of 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1mmol) in 2-pentanol (5 ml) and the mixture stirred at 120° C. for 2hours. The mixture was allowed to cool and the resulting precipitate wascollected by filtration, washed with isopropanol and then ether anddried under vacuum at 70° C. to give7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinaxolinehydrochloride (33 1 mg, 80%). ¹H NMR Spectrum: (DMSOd₆) 2.16(s, 3H);5.36(s, 2H); 6.88(d, 1H); 7.12(d, 1H); 7.3-7.65(m, 7H); 8.68(d, 1H);8.82(s, 1H); 9.68(s, 1H); 11.4(s, 1H) MS-ESI: 376 [MH]⁺

Elemental analysis: Found C 63.7 H 4.8 N 10.0 C₂₂H₁₈N₃O₂F 1 HCl RequiresC 64.2 H 4.7 N 10.2%

The starting material was prepared as follows:

Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96mmol) andthe mixture was heated at 148° C. for 30 minutes.7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc.section B 1967, 449), was added and the mixture maintained at 148° C.for 24 hours. The reaction mixture was allowed to cool, the solution waspoured on to water (170 ml) and the aqueous mixture adjusted to pH3 withconcentrated hydrochloric acid. The precipitate was collected byfiltration, washed with water, ether and dried under vacuum to give7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.m.p. 267-269° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 5.32(s, 2H); 7.25(d,1H); 7.32-7.52(m, 6H); 8.12(d, 1H); 8.99(s, 1H) MS-ESI: 252 [MH]⁺

Elemental analysis: Found C 71.4 H 4.9 N 10.7 C₁₅H₁₂N₂O₂ 0.04 H₂ORequires C 71.2 H 4.8 N 11.1%

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (800 mg, 3.17 mmol)and DMF (100 μl) in thionyl chloride (20 ml, 0.27 mmol) was heated atreflux for 3 hours. Excess thionyl chloride was removed by evaporationand the residue azeotroped with toluene and dried under vacuum to give7-benzyloxy-4-chloroquinazoline hydrochloride (835 mg, 86%) as a creamsolid. m.p. 131-132° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 5.32(s, 2H);7.29(d, 1H); 7.34-7.52(m, 6H); 8.12(d, 1H); 9.03(s, 1H) MS-ESI: 270[MH]⁺

EXAMPLE 71

Using an analogous procedure to that described in Example 70,7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol),(prepared as described for the starting material in Example 70), wastreated with 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (EP061741 A2), to give7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazolinehydrochloride (407 mg, 94%). m.p. 253-257° C. ¹H NMR Spectrum: (DMSOd₆)5.37(s, 2H); 7.16(d, 1H); 7.32-7.5(m, 4H); 7.54(s, 1H); 7.56(d, 2H);7.59(dd, 1H); 8.73(d, 1H); 8.86(s, 1H); 10.63(br s, 1H); 11.6(br s, 1H)MS-ESI: 396 [MH]⁺

Elemental analysis: Found C 57.8 H 3.8 N 9.7 C₂₁H₁₅N₃O₂ClF 0.3 H₂O 1 HClRequires C 57.6 H 3.8 N 9.6%

EXAMPLE 72

Using an analogous procedure to that described in Example 36,4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (224 mg, 0.6 mmol), (prepared as described for thestarting material in Example 22), was treated with4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72 mmol) to give7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolinehydrochloride (90 mg, 31%). ¹H NMR Spectrum: (DMSOd₆) 2.17(s, 3H);4.0(s, 3H); 5.33(s, 2H); 6.88(d, 1H); 7.11(d, 1H); 7.38(s, 1H); 7.41(m,1H); 7.55(m, 1H); 7.62(m, 1H); 8.17(s, 1H); 8.75(s, 1H); 9.68(s, 1H);11.15(s, 1H) MS-ESI: 442 [MH]⁺

Elemental analysis: Found C 58.0 H 4.3 N 8.7 C₂₃H₁₈N₃O₃F₃ 0.9 HCl 0.08Requires C 58.3 H 4.1 N 8.8 isopropanol

EXAMPLE 73

Tetrabutylammonium fluoride (563 μl of a 1M solution in THF, 0.62 mmol)was added to a solution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline(207 mg, 0.31 mmol) in THF (5 ml) cooled at 5° C. and the mixture wasthen stirred for 1hour at ambient temperature. Water was added and thevolatiles were removed by evaporation. The solid residue was dissolvedin methylene chloride/methanol and a 5M solution of hydrogen chloride inisopropanol (0.3 ml) was added. The solvent was removed by evaporation,the solid residue was resuspended in ether, collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazolinehydrochloride (99 mg, 63%). ¹H NMR Spectrum: (DMSOd₆) 3.93(s, 3H);4.01(s, 3H); 5.67(s, 2H); 7.16(d, 1H); 7.52(d, 1H); 7.58(s, 1H); 7.70(s,1H); 7.78(s, 1H); 8.31(s, 1H); 8.8(s, 1H); 10.58(s, 1(s, 1H); 11.35(brs, 1H) MS-ESI: 430 [MH]⁺

Elemental analysis: Found C 45.8 H 4.3 N 12.9 C₂₀H₁₇N₅O₃ClF 1.4H₂O 2HClRequires C 45.5 H 4.2 N 13.3%

The starting material was prepared as follows:

Diethyl azodicarboxylate (219 μl, 1.4 mmol) was added dropwise to asolution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(400 mg, 0.7 mmol), (prepared as described for the starting material inExample 33), 2-hydroxymethyl-1-methylimidazole (82 mg, 0.83 mmol), (J.Chem. Soc. 1927, 3128-3136), and triphenylphosphine (365 mg, 1.4 mmol)in methylene chloride (12 ml) cooled at 0° C. The mixture was stirredfor 1 hour at ambient temperature and further2-hydroxymethyl-1-methylimidazole (68 mg, 0.69 mmol), triphenylphosphine(91 mg, 0.34 mmol) and diethyl azodicarboxylate (54 μl, 0.34 mmol) wereadded. The mixture was stirred for 1 hour at ambient temperature and thesolvent was removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (94/6) to give4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline(116 mg, 25%). ¹H NMR Spectrum: (CDCl₃) 1.16(s, 9H); 3.75(s, 3H);3.93(s, 3H); 5.28(s, 2H); 6.84(s, 1H); 6.91(s, 1H); 7.02(s, 1H); 7.17(d,1H); 7.32-7.48(m, 8H); 7.78(2d, 4H); 8.08(s, 1); 8.18(d, 1H)

EXAMPLE 74

A mixture of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazolinehydrochloride (400 mg, 0.98 mmol), 2-chloromethyl-1-methylimidazolehydrochloride (210 mg, 1.25 mmol), potassium carbonate (580 mg, 4.2mmol) and potassium iodide (17 mg, 0.1 mmol) in DMF (20 ml) was stirredat 65° C. for 4.5 hours followed by 17 hours at ambient temperature. Thesolvent was removed by evaporation and the residue was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water, brine, dried (MgSO₄) and the solvent removed by evaporation.The solid residue was purified by column chromatography eluting withmethylene chloride/methanol (97/3) to give a yellow solid (258 mg). Thissolid was dissolved in methanol (5 ml) and a 1M aqueous sodium hydroxidesolution (660 μl, 0.66 mmol) was added. The mixture was stirred for 15minutes, then water was added and the mixture adjusted to pH7 withconcentrated hydrochloric acid. The aqueous mixture was extracted withethyl acetate and the combined organic extract was washed with water,brine, dried (MgSO₄) and the solvent removed by evaporation. The residuewas purified by flash chromatography eluting with methylenechloride/methanol (95/5). The purified solid product was dissolved inmethanol and methanolic hydrogen chloride (1.5 ml of a 7.5M solution)was added. The volatiles were removed by evaporation, the solid residuewas suspended in pentane, collected by filtration, washed with pentaneand dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((1-methylimidazol-2-yl)methoxy)quinazolinehydrochloride (105 mg, 44%). ¹H NMR Spectrum: (DMSOd₆) 2.16(s, 3H);3.92(s, 3H); 5.71(s, 2H); 6.90(d, 1H); 7.1(d, 1H); 7.52(d, 1H); 7.64(d,1H); 7.71(s, 1H); 7.78(s, 1H); 8.77(d, 1H); 8.82(s, 1H); 9.7(br s, 1H);1.45(br s, 1H) MS-ESI: 380 [MH]⁺

Elemental analysis: Found C 52.2 H 5.0 N 15.1 C₂₀H₁₈N₅O₂F 0.9H₂O 1.8HClRequires C 52.1 H 4.7 N 15.2%

The starting material was prepared as follows:

Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol)and the mixture was heated at 148° C. for 30 minutes,7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc.section B 1967, 449), was added and the mixture maintained at 148° C.for 24 hours. The reaction mixture was allowed to cool, the solution waspoured on to water (170 ml) and the aqueous mixture adjusted to pH3 withconcentrated hydrochloric acid. The precipitate was collected byfiltration, washed with water, then ether and dried under vacuum to give7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.m.p. 267-269° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 5.32(s, 2H); 7.25(d,1H); 7.32-7.52(m, 6H); 8.12(d, 1H); 8.99(s, 1H) MS-ESI: 252 [MH]⁺

Elemental analysis: Found C 71.4 H 4.9 N 10.7 C₁₅H₁₂N₂O₂0.04H₂O RequiresC 71.2 H 4.8 N 11.1%

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (800 mg, 3.177mmol) and DMF (100 μl) in thionyl chloride (20 ml, 0.27 mmol) was heatedat reflux for 3 hours. Excess thionyl chloride was removed byevaporation and the residue azeotroped with toluene and dried undervacuum to give 7-benzyloxy-4-chloroquinazoline hydrochloride (835 mg,86%) as a cream solid. m.p. 131-132° C. ¹H NMR Spectrum: (DMSOd₆;CF₃COOD) 5.32(s, 2H); 7.29(d, 1H); 7.34-7.52(m, 6H); 8.12(d, 1H);9.03(s, 1H) MS-ESI: 270 [MH]⁺

2-Fluoro-5-methoxycarbonyloxy-4-methylaniline (883 mg, 4.4 mmol),(prepared as described for the starting material in Example 12), wasadded to a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (1g, 3.7 mmol) in 2-pentanol (15 ml) at 120° C. and the mixture was thenheated at reflux for 4 hours. The mixture was allowed to cool and theprecipitate was collected by filtration, washed with isopropanolfollowed by ether and dried under vacuum to give7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazolinehydrochloride (1.65 g, 97%) as a cream solid. m.p. 219-220° C. ¹H NMRSpectrum: (DMSOd₆) 2.22(s, 3H); 3.86(s, 3H); 5.37(s, 2H); 7.30-7.60(m,9H); 8.60(d, 1H); 8.80(s, 1H); 11.2(s, 1H) MS-ESI: 434 [MH]⁺

Elemental analysis: Found C 60.1 H 4.9 N 8.5 C₂₄H₂₀N₃O₄F 1HCl 0.5H₂ORequires C 60.2 H 4.6 N 8.8%

7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazolinehydrochloride (1.53 g, 3.25 mmol) and 10% palladium-on-charcoalcatalyst-(180 mg) in a mixture of methanol (75 ml), DMF (6 ml) andtrichloromethane (30 ml) was stirred under hydrogen at 1.5 atmospherespressure for 45 minutes. The catalyst was removed by filtration throughdiatomaceous earth and the solvent removed from the filtrate byevaporation. The residue was triturated with ether, the resulting solidwas collected by filtration and dried under vacuum to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazolinehydrochloride (1.23 g, 84%) as an orange solid. m.p. 205-210° C. ¹H NMRSpectrum: (DMSOd₆) 2.22(s, 3H); 3.85(s, 3H); 7.24(d, 1H); 7.35(dd, 1H);7.42(d, 1H); 7.45(d, 1H); 8.58(d, 1H); 8.81(s, 1H); 11.40(s, 1H);11.76(s, 1H) MS-ESI: 344 [MH]⁺

EXAMPLE 75

Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added dropwise to asuspension of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazolinehydrochloride (261 mg, 0.7 mmol), (prepared as described for thestarting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol)and 2-(1,2,4-triazol-1-yl)ethanol (95 mg, 0.84 mmol), (Ann. Pharm. Fr.1977, 35, 503-508), in methylene chloride (5 ml). The mixture wasstirred for 1 hour at ambient temperature and further triphenylphosphine(184 mg, 0.7 mmol), 2-(1,2,4-triazol-1-yl)ethanol (63 mg, 0.56 mmol) anddiethyl azodicarboxylate (122 mg, 0.7 mmol) were added. The mixture wasstirred for a further 2.5 hours and the solvent was removed byevaporation. The residue was dissolved in methanol (5 ml) and 2M aqueoussodium hydroxide solution (2 ml) was added. The mixture was stirred for20 minutes and the mixture was partitioned between ether and water. Theaqueous layer was acidified to pH7 with 2M hydrochloric acid and theresulting precipitate was collected by filtration, washed with water,and dried under vacuum. The resulting solid was dissolved in methylenechloride/methanol and a 5M solution of hydrogen chloride in isopropanol(0.5 ml) was added. The volatiles were removed by evaporation, the solidwas resuspended in ether, collected by filtration, washed with ether anddried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazolinehydrochloride (180 mg, 56%). ¹H NMR Spectrum: (DMSOd₆) 2.16(s, 3H);3.97(s, 3H); 4.59(t, 2H); 4.74(t, 2H); 6.9(d, 1H); 7.10(d, 1H); 7.37(s,1H); 8.03(s, 1H); 8.23(s, 1H); 8.62(s, 1H); 8.79(s, 1H); 9.7(br s, 1H);11.4(s, 1H) MS-ESI: 411 [MH]⁺

Elemental analysis: Found C 53.2 H 4.8 N 18.4 C₂₀H₁₉N₆O₃F 0.1H₂O 1.2HClRequires C 52.7 H 4.5 N 18.4%

EXAMPLE 76

Tetrabutylammonium fluoride (608 μl of a 1M solution in THF, 0.67 mmol)was added to a solution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline(224 mg, 0.33 mmol) in THF (5 ml) cooled at 5° C. After stirring for 1hour at ambient temperature, water was added. The THF was removed byevaporation. The precipitate was collected by filtration and dried byazeotroping with ethanol. The solid was dissolved in methylenechloride/methanol and a solution of 5M hydrochloric acid in isopropanolwas added. The volatiles were removed by evaporation. The residue wassuspended in ether, collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazolinehydrochloride (132 mg, 85%). m.p. 277-281° C. ¹H NMR Spectrum: (DMSOd₆)3.99(s, 3H); 5.34(s, 2H); 7.15(d, 1H); 7.26(d, 1H); 7.49(s, 1H); 7.53(d,1H); 7.61(m, 1H); 7.75(s, 1H); 8.22(s, 1H); 8.8(s, 1H); 10.59(s, 1H);11.38(br s, 1H) MS-ESI: 432 [MH]⁺

Elemental analysis: Found C 51.0 H 3.5 N 8.9 C₂₀H₁₅N₃O₃ClFS 0.1H₂O 1HClRequires C 51.1 H 3.5 N 8.9%

The starting material was prepared as follows:

Diethyl azodicarboxylate (274 μl, 1.7 mmol) was added dropwise to asolution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(400 mg, 0.7 mmol), (prepared as described for the starting material inExample 33), 3-thiophenemethanol (119 mg, 1 mmol) triphenylphosphine(456 mg, 1.7 mmol) in methylene chloride (12 ml) cooled at 0° C. Themixture was stirred for 2 hours at ambient temperature, the solvent wasremoved by evaporation and the residue was purified by columnchromatography eluting with methylene chloride/ether (95/5). Thepurified product was triturated with petroleum ether/ethyl acetate (8/2)and the solid product was collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline(223 mg, 47%). ¹H NMR Spectrum: (DMSOd₆) 1.09(s, 9H); 3.85(s, 3H);5.23(s, 2H); 7.04(d, 1H); 7.21(d, 1H); 7.25(s, 1H); 7.4-7.5(m, 6H);7.58(m, 2H); 7.62-7.75(m, 6H); 8.1(s, 1H); 9.22(br s, 1H)

EXAMPLE 77

Diethyl azodicarboxylate (274 μl, 1.7 mmol) was added dropwise to asolution of4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(400 mg, 0.7 mmol), (prepared as described for the starting material inExample 33), triphenylphosphine (456 ml, 1.7 mmol), 2-(4-pyridyl)ethanol(128 mg, 1 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), inmethylene chloride (12 ml) cooled at 0° C. The mixture was stirred for 2hours at ambient temperature and the solvent was removed by evaporation.The residue was purified by column chromatography eluting with methylenechloride/methanol (97/3) to give a white solid (416 mg). A portion ofthis solid (390 mg) was dissolved in THF (6 ml), the solution was cooledto 0° C. and tetrabutylammonium fluoride (1.1 ml of a 1M solution inTHF, 1.1 mmol) was added and the mixture was stirred for 2 hours atambient temperature. Water was added, the organic solvent was removed byevaporation and the resulting precipitate was collected by filtration.The solid was dissolved in methylene chloride/methanol and a 5M solutionof hydrogen chloride in isopropanol (0.5 ml) was added. The volatileswere removed by evaporation and the solid was resuspended in isopropanoland collected by filtration, washed with isopropanol and ether and driedunder vacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazolinehydrochloride (123 mg, 42%). ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 3.49(t,2H); 3.99(s, 3H); 4.6(t, 2H); 7.16(d, 1H); 7.41(s, 1H); 7.51(d, 1H);8.05(br s, 2H); 8.19(s, 1H); 8.84(s, 1H); 8.86(br s, 2H) MS-ESI: 441[MH]⁺

Elemental analysis: Found C 50.4 H 4.7 N 10.0 C₂₂H₁₈N₄O₃ClF 1.1H₂O1.8HCl Requires C 50.5 H 4.5 N 10.4% 0.23 isopropanol

EXAMPLE 78

Using an analogous procedure to that described in Example 77,4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(300 mg, 0.52 mmol), (prepared as described for the starting material inExample 33), was treated with 4-hydroxymethyl-2-methylthiazole (100 mg,0.87 mmol) to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazolinehydrochloride (132 mg, 52%). ¹H NMR Spectrum: (DMSOd₆) 2.68(s, 3H);4.00(s, 3H); 5.35(s, 2H); 7.17(d, 1H); 7.52(d, 1H); 7.56(s, 1H); 7.72(s,1H); 8.29(s, 1H); 8.83(s, 1H); 10.63(br s, 1H); 11.58(s, 1H) MS-ESI: 447[MH]⁺

Elemental analysis: Found C 48.2 H 3.7 N 11.2 C₂₀H₁₆N₄O₃ClFS 0.6H₂O1.2HCl Requires C 47.9 H 3.7 N 11.2%

The starting material was prepared as follows:

A solution of 4-chloromethyl-2-methylthiazole (1.84 g, 10 mmol) in water(9 ml) and concentrated hydrochloric acid (2 ml) was heated at refluxfor 20 hours. The mixture was allowed to cool and was adjusted to pH5with 2M aqueous sodium hydroxide solution and the mixture was extractedwith ethyl acetate. The organic extract was washed with water and brine,dried (MgSO₄) and the solvent removed by evaporation. The residue waspurified by column chromatography eluting with methylenechloride/methanol (97/3) to give 4-hydroxymethyl-2-methylthiazole (800mg, 54%). ¹H NMR Spectrum (CDCl₃) 2.72(s, 3H); 2.92(br s, 1H); 4.73(s,2H); 7.03(s, 1H)

EXAMPLE 79

Diethyl azodicarboxylate (197 μl, 1.2 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(200 mg, 0.6 mmol), (prepared as described for the starting material inExample 24), 3-thiophenemethanol (107 mg, 0.93 mmol) andtriphenylphosphine (328 mg, 1.2 mmol) in methylene chloride (6 ml)cooled at 0° C. The mixture was stirred for 2 hours at ambienttemperature and further triphenylphosphine (157 mg, 0.57 mmol),3-thiophenemethanol (107 mg, 0.93 mmol) and diethyl azodicarboxylate(98.5 μl , 0.59 mmol) were added. The mixture was stirred for 2 hours atambient temperature and the solvent was removed by evaporation. Theresidue was dissolved in ethyl acetate and the solution was washed withwater and brine, dried (MgSO₄) and the solvent removed by evaporation.The residue was purified by column chromatography eluting with methylenechloride/ethyl acetate (4/6). The resulting oil was dissolved in etherand a 5M solution of hydrogen chloride in isopropanol (1 ml) was added.The resulting precipitate was collected by filtration, washed with etherand dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazolinehydrochloride (59 mg, 20%). ¹H NMR Spectrum: (DMSOd₆) 3.99(s, 3H);5.34(s, 2H); 7.25(d, 1H); 7.43(d, 1H); 7.45(s, 1H); 7.58-7.63(m, 2H);7.7(dd, 1H); 7.72(dd, 1H); 8.17(s, 1H); 8.78(s, 1H) MS-ESI: 416 [MH]⁺

Elemental analysis: Found C 53.5 H 3.7 N 9.0 C₂₀H₁₅N₃O₂ClFS 0.95HClRequires C 53.3 H 3.6 N 9.3%

EXAMPLE 80

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(250 mg, 0.78 mmol), (prepared as described for the starting material inExample 24), 2-acetamido-4-chloromethylthiazole (164 mg, 0.86 mmol) andpotassium carbonate (216 mg, 1.5 mmol) in DMF (5 ml)was stirred at 40°C. for 7 hours. The mixture was partitioned between ethyl acetate andwater and the aqueous layer was adjusted to pH7 with 2M hydrochloricacid. The organic phase was washed with water, brine, dried (MgSO₄) andthe solvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (95/5). Thepurified solid was dissolved in a mixture of methylene chloride andmethanol and a 5M solution of hydrogen chloride in isopropanol (1.0 ml)was added. The volatiles were removed by evaporation to give a solid,which was triturated with ether, collected by filtration and dried undervacuum to give7-((2-acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (96 mg, 24%). m.p. 194-202° C. ¹H NMR Spectrum: (DMSOd₆)2.14(s, 3H); 4.0(s, 3H); 5.31(s, 2H); 7.34(s, 1H); 7.45(dd, 1H); 7.52(s,1H); 7.60(t, 1H); 7.68(dd, 1H); 8.30(s, 1H); 8.81(s, 1H) MS-ESI: 474[MH]⁺

Elemental analysis: Found C 46.9 H 3.8 N 13.2 C₂₁H₁₇N₅O₃ClFS 1.1H₂O1.1HCl Requires C 47.3 H 3.8 N 13.1%

EXAMPLE 81

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(300 mg, 0.93 mmol), (prepared as described for the starting material inExample 24), 2-(1,2,4-triazol-1-yl)ethanol (159 mg, 1.4 mmol), (Ann.Pharm. Fr. 1977, 35, 503-508), and triphenylphosphine (492 mg, 1.8 mmol)in methylene chloride (10 ml). The mixture was stirred for 2 hours atambient temperature and further triphenylphosphine (246 mg, 0.9 mmol)and diethyl azodicarboxylate (147 μl, 0.9 mmol) were added. The mixturewas stirred for 1 hour at ambient temperature and the resultingprecipitate was collected by filtration, washed with methylene chlorideand ether and dried under vacuum. This solid was suspended in methylenechloride/methanol and a 5M solution of hydrogen chloride in isopropanol(1.0 ml) was added. The volatiles were removed by evaporation, theresidue was triturated with ether. The resulting solid was collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazolinehydrochloride (219 mg, 52%). m.p. 169-174° C. ¹H NMR Spectrum: (DMSOd₆)3.99(s, 3H); 4.60(t, 2H); 4.74(t, 2H); 7.43(d, 1H); 7.45(s, 1H); 7.59(t,1H); 7.67(dd, 1H); 8.06(s, 1H); 8.41(s, 1H); 8.68(s, 1H); 8.83(s, 1H)MS-ESI: 415 [MH]⁺

Elemental analysis: Found C 47.0 H 4.3 N 16.5 C₁₉H₁₆N₆O₂ClF 1.6H₂O 1HClRequires C 47.0 H 4.4 N 16.4% 0.35 isopropanol

EXAMPLE 82

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asolution of 1-(3-hydroxypropyl)-[1,2,4]-triazole (119 mg, 0.93 mmol),(EP0060696 A1),4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.62 mmol), (prepared as described for the starting material in Example24), and triphenylphosphine (492 g, 1.8 mmol) in methylene chloride (4ml) and the mixture stirred for 3 hours at ambient temperature. Themixture was purified by column chromatography eluting with methylenechloride/acetonitrile/methanol (60/32/8). The purified product wastriturated with a mixture of pentane and ether, collected by filtrationand dried under vacuum to give a white solid. This solid was dissolvedin methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a5M solution) was added. The volatiles were removed by evaporation. Thesolid residue was suspended in ether, collected by filtration, washedwith ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)quinazolinehydrochloride (121 mg, 39%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.44(t,2H); 4.0(s, 3H); 4.3(t, 2H); 4.5(t, 2H); 7.32(s, 1H); 7.47(dd, 1H);7.62(t, 1H); 7.70(dd, 1H); 8.08(s, 1H); 8.41(s, 1H); 887(s,1H); 9.10(s,1H) MS-ESI: 429 [MH]⁺

Elemental analysis: Found C 47.8 H 4.2 N 16.6 C₂₀H₁₈N₆O₂ClF 0.2 H₂O 2HCl Requires C 47.5 H 4.1 N 16.6%

EXAMPLE 83

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (314 mg, 1.2 mmol) and2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) inmethylene chloride (5 ml) and the mixture stirred for 2 hours at ambienttemperature. The solvent was removed by evaporation, the residue wastriturated with ether and the resulting solid was collected byfiltration. The solid was purified by column chromatography eluting withmethylene chloride/methanol (9/1 followed by 8/2) to give a white solid.This solid was dissolved in methylene chloride/methanol and etherealhydrogen chloride (0.5 ml of a 4M solution) was added. The volatileswere removed by evaporation, the residue was triturated with ether,collected by filtration and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazolinehydrochloride (110 mg, 60%). 1H NMR Spectrum: (DMSOd₆) 3.11(s, 3H);3.89(s, 3H); 3.94(t, 2H); 4.37(t, 2H); 6.85(dd, 1H); 7.21(s, 1H);7.35(dd, 1H); 7.55(dd, 1H); 7.59(t, 1H); 7.8(s, 1H); 8.36(s, 1H);8.59(d, 1H); 8.90(d, 1H); 9.57(s, 1H)

Elemental analysis: Found C 47.2 H 4.6 N 14.7 C₂₂H₂₀N₆O₂ClF 1.5 H₂ORequires C 47.2 H 4.5 N 15.0% 2.15 HCl

The starting material was prepared as follows:

A solution of 4-bromo-3,6-dichloro-pyridazine (1.11 g, 5 mmol), (J.Chem.Soc., Perkin Trans I, 1974, 696), and 2-(methylamino)ethanol (0.75 g, 10mmol) in isopropanol (10 ml) was heated at reflux for 30 minutes. Thesolvent was removed by evaporation, the residue was partitioned betweenmethylene chloride and water and the aqueous layer was adjusted to pH9with solid potassium carbonate. The organic layer was separated, washedwith brine, dried (MgSO₄) and the solvent removed by evaporation. Theresidue was triturated with ether, collected by filtration and driedunder vacuum to give2-(N-(3,6-dichloropyridazin-4-yl)-N-methylanilino)ethanol (1 g, 90%). ¹HNMR Spectrum: (CDCl₃) 2.1(br s, 1H); 3.09(s, 3H); 3.71(t, 2H); 3.93(t,2H); 6.8(s, 1H) MS-ESI: 221 [MH]⁺

A mixture of 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol(444 mg, 2 mmol) and 10% palladium-on-charcoal catalyst (150 mg) inethanol (15 ml), methanol (5 ml) and aqueous ammonia (15 ml) was stirredunder hydrogen at 3 atmospheres pressure for 4 hours. The catalyst wasremoved by filtration and the solvent removed from the filtrate byevaporation. The residue was dissolved in methylene chloride, theinsoluble material was removed by filtration and the solvent was removedfrom the filtrate by evaporation. The residue was purified by columnchromatography on neutral aluminum oxide eluting with methylenechloride/methanol (95/5 followed by 90/10). The purified product wastriturated with petroleum ether, the solid product was collected byfiltration and dried under vacuum to give2-N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg, 91%). ¹H NMRSpectrum: (CDCl₃) 3.06(s, 3H); 3.57(t, 2H); 3.89(t, 2H); 6.52(dd, 1H);8.48(d, 1H); 8.54 (d, 1H) MS-ESI: 153 [MH]⁺

EXAMPLE 84

2M Aqueous sodium hydroxide solution (560 μl, 1.1 mmol) was added to asolution of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline(250 mg, 0.56 mmol) in methanol (7 ml) cooled at 0° C. and the mixturethen stirred for 1 hour at ambient temperature. The mixture was dilutedwith water and the mixture adjusted to pH6 with 2M hydrochloric acid.The resulting solid was collected by filtration, washed with water anddried under vacuum. The solid was dissolved in methylenechloride/methanol and isopropanolic hydrogen chloride (0.7 ml of a 5Msolution) was added. The volatiles were removed by evaporation, thesolid residue was triturated with ether, collected by filtration, washedwith ether and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazolinehydrochloride (241 mg, 93%). MS-ESI: 390 [MH]⁺ ¹H NMR Spectrum: (DMSOd₆;CFCOOD) 2.2(s, 3H); 6.94(d, 1H); 7.13(d, 1H); 8.18(d, 1H); 8.53(d, 2H);8.68(s, 1H); 8.77(d, 1H); 8.94(s, 1H); 9.20(d, 2H)

Elemental analysis: Found C 52.0 H 4.3 N 14.3 C₂₁H₁₆N₅O₂F 1.2 H₂O 1.95HCl Requires C 52.3 H 4.3 N 14.5%

The starting material was prepared as follows:

A mixture of 7-nitro-3,4-dihydroquinazolin-4-one (J. Chem. Soc. 1950,1104-1111) (5 g, 26 mmol) in thionyl chloride (50 ml) and DMF (1 ml) washeated at reflux for 1.5 hours. Excess thionyl chloride was removed byevaporation and the residue azeotroped with toluene. The residue wassuspended in ether, collected by filtration and dried under vacuum togive 4-chloro-7-nitroquinazoline hydrochloride (6.4 g, 100%). ¹H NMRSpectrum: (DMSOd₆) 8.26(dd, 1H); 8.36(d, 1H); 8.40(s, 1H); 8.42(dd, 1H)MS-ESI: 209 [MH]⁺

A solution of 4-chloro-7-nitroquinazoline hydrochloride (2.46 g, 10mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.2 g, 1 mmol),(prepared as described for the starting material in Example 12), inisopropanol (25 ml) was heated at 50° C. for 1 hour. The mixture wasallowed to cool, the precipitated solid was collected by filtrationrecrystallised from methylene chloride/methanol/isopropanol to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazolinehydrochloride (1.8 g, 45%) as a yellow solid. ¹H NMR Spectrum: (DMSOd₆)2.21(s, 3H); 3.86(s, 3H); 7.40(d, 1H); 7.46(d, 1H); 8.49(dd, 1H);8.63(s, 1H); 8.84(s, 1H); 8.89(d, 1H) MS-ESI: 373 [MH]⁺

Elemental analysis: Found C 50.0 H 3.6 N 13.8 C₁₇H₁₃N₄O₅F 1 HCl RequiresC 50.0 H 3.5 N 13.7%

A mixture of4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)7-nitroquinazolinehydrochloride (5.3 g, 13 mmol) and 10% palladium-on-charcoal catalyst (1g) in ethanol (10 ml), ethanolic hydrogen chloride (1.8 ml of a 7Msolution) and methanol (20 ml) was stirred under hydrogen at 1.7atmospheres pressure for 75 minutes. The catalyst was removed byfiltration through diatomaceous earth and the filter pad thoroughlywashed with methylene chloride, methanol and ether and the solvent wasremoved from the filtrate by evaporation to give7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazolinehydrochloride (4.8 g, 97%) as a yellow solid. ¹H NMR Spectrum: (DMSOd₆)2.22(s, 3H); 3.87(s, 3H); 6.77(s, 1H); 7.08(dd, 1H); 7.15(m, 2H);7.41(m, 2H); 8.35(d, 1H); 8.63(s, 1H); 11.03(s, 1H) MS-ESI: 343 [MH]⁺

A solution of7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazolinehydrochloride (0.45 g, 1.2 mmol) and isonicotinoyl chloridehydrochloride (296 mg, 1.66 mmol) in pyridine (15 ml) was stirred for 2hours at ambient temperature, followed by 1 hour at 40° C. Furtherisonicotinoyl chloride hydrochloride (84 mg, 0.46 mmol) was added andthe mixture was stirred at 40° C. for 2 hours. The volatiles wereremoved by evaporation, the mixture was diluted with water. The aqueousmixture was adjusted to pH7 and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried (MgSO₄) and the solventremoved by evaporation. The residue was purified by flash chromatographyeluting with methylene chloride/methanol (95/5 followed by 92/8). Thepurified solid was triturated with ether, collected by filtration,washed with ether and dried under vacuum to give4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline(264 mg, 49%). ¹NMR Spectrum: (DMSOd₆) 2.19(s, 3H); 3.86(s, 3H); 7.31(d,1H); 7.45(d, 1H); 7.92(d, 2H); 7.98(d, 1H); 8.31(s, 1H); 8.43(d, 1H);8.47(s, 1H); 8.83(d, 2H); 9.78(br s, 1H); 10.89(br s, 1H)

EXAMPLE 85

4-Chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added to a solution of4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazolinehydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) and the mixtureheated at reflux for 1 hour. The solvent was removed by evaporation andthe residue was partitioned between ethyl acetate and saturated aqueoussodium hydrogen carbonate solution. The organic layer was separated,washed with brine, dried (MgSO₄) and the solvent removed by evaporation.The residue was purified by flash chromatography eluting with methylenechloride/methanol (95/5). The purified solid was dissolved in methylenechloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution)was added. The volatiles were removed by evaporation, the residue wastriturated with ether, collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazolinehydrochloride (75 mg, 39%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.46 and2.47(2s, 3H); 3.35 and 3.42(2s, 3H); 3.97 and 3.98 (2s, 3H); 4.2(br s,1H); 4.3(br s, 1H); 4.5(br s, 2H); 7.05 and 7.3(2s, 1H); 7.4 and 7.5(m,2H); 7.62(t, 1H); 7.7(d, 1H); 8.25(br s, 1H); 8.8 and 8.9(2s, 2H)MS-ESI: 469 [MH]⁺

The starting material was prepared as follows:

Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) wasadded in portions over 20 minutes to a solution of7-benzyloxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), (prepared asdescribed for the starting material in Example 70), in DMF (70 ml) andthe mixture stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5mmol) was added dropwise and the mixture stirred 2 hours at ambienttemperature. The mixture was diluted with ethyl acetate (100 ml) andpoured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). Theorganic layer was separated and the aqueous layer extracted with ethylacetate, the combined extracts were washed with brine, dried (MgSO₄) andthe solvent removed by evaporation. The residue was triturated with amixture of ether and petroleum ether, the solid was collected byfiltration and dried under vacuum to give7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(10 g, 84%). ¹H NMR Spectrum: (DMSOd₆) 1.11(s, 9H); 3.89(s, 3H); 5.3(s,2H); 5.9(s, 2H); 7.27(s, 1H); 7.35(m, 1H); 7.47(t, 2H); 7.49(d, 2H);7.51(s, 1H); 8.34(s, 1H)

A mixture of7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(7 g, 17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg) inethyl acetate (250 ml), DMF (50 ml), methanol (50 ml) and acetic acid(0.7 ml) was stirred under hydrogen at atmospheric pressure for 40minutes. The catalyst was removed by filtration and the solvent removedfrom the filtrate by evaporation. The residue was triturated with ether,collected by filtration and dried under vacuum to give7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(4.36 g, 80%). ¹H NMR Spectrum: (DMSOd₆) 1.1(s, 9H); 3.89(s, 3H);5.89(s, 2H); 7.0(s, 1H); 7.48(s, 1H); 8.5(s, 1H)

Diethyl azodicarboxylate (679 mg, 3.9 mmol) was added dropwise to asuspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(918 mg, 3 mmol), triphenylphosphine (1 g, 3.9 mmol) and2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (682 mg, 3.9 mmol),prepared as described below, in methylene chloride (20 ml) and themixture stirred for 1 hour at ambient temperature. Further2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (105 mg, 0.6 mmol),triphenylphosphine (786 mg, 3 mmol) and diethyl azodicarboxylate (522mg, 3 mmol) were added and the mixture stirred for 30 minutes at ambienttemperature. The mixture was concentrated to half volume by evaporationand purified by column chromatography eluting with methylenechloride/ether (7/3 increasing to 1/1) to give6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.3 g, 98%). ¹H NMR Spectrum: (CDCl₃) 1.2(s, 9H); 1.45(s, 9H); 3.05(brs, 3H); 3.72(br s, 2H); 3.98(s, 3H); 4.25(br s, 2H); 5.95(s, 2H); 7.1(brs, 1H); 7.6(s, 1H); 8.2(s, 1H)

A solution of6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.39 g, 3 mmol) in methylene chloride (4 ml) and TFA (4 ml) was stirredat ambient temperature for 1 hour. Toluene was added, and the volatileswere removed by evaporation. The residue was triturated with ether andthe resulting solid was collected by filtration. The solid was dissolvedin water, sodium hydrogen carbonate was added and the aqueous mixturewas extracted with methylene chloride. The organic extract was dried(MgSO₄) and the solvent removed by evaporation. The residue wastriturated with ether and the solid was collected by filtration to give6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(800 mg, 73%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.13(s, 9H); 2.72(s,3H); 3.45(br s, 2H); 3.95(br s, 3H); 4.5(t, 2H); 5.94(s, 2H); 7.31(s,1H); 7.6(s, 1H); 8.47(s, 1H) MS-ESI: 364 [MH]⁺

A solution of6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(363 mg, 1 mmol) and 4-chloro-6-methylpyrimidine (257 mg, 2 mmol), (J.Het. Chem., 1969, 6, 879), in N,N-diisopropylethylamine (2 ml) washeated at reflux for 30 minutes. The volatiles were removed byevaporation and the residue was partitioned between ethyl acetate andwater. The organic layer was separated, washed with brine, dried (MgSO₄)and the solvent removed by evaporation. The residue was purified bycolumn chromatography eluting with methylene chloride/methanol (95/5) togive6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(365 mg, 80%). ¹H NMR Spectrum: (CDCl₃) 1.19(s, 9H); 2.36(s, 3H);3.18(s, 3H); 3.95(s, 3H); 4.09(t, 2H); 4.34(t, 2H); 5.9(s, 2H); 6.3(s,1H); 7.14(s, 1H); 7.63(s, 1H); 8.17(s, 1H); 8.5(s, 1H) MS-ESI: 456 [MH]⁺

A solution of6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(365 mg, 0.8 mmol) in methanolic ammonia (30 ml of a 3M solution) wasstirred at ambient temperature for 16 hours. The volatiles were removedby evaporation, the residue was triturated with ether, the solid wascollected by filtration, washed with ether and dried under vacuum togive6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-one(250 mg, 92%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.44(s, 3H); 3.32 and3.39(2s, 3H); 3.86 and 3.87(2s, 3H); 4.12(t, 1H); 4.25(t, 1H); 4.42(m,2H); 7.02 and 7.23(2s, 1H); 7.24(t, 1H); 7.50(s, 1H); 8.55 and 8.8(2m,1H); 8.78 and 8.80(2s, 1H) MS-ESI: 342 [MH]⁺

A mixture of6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-one(250 mg, 0.73 mmol) in thionyl chloride (5 ml) and DMF (0.1 ml) washeated at reflux for 1 hour. The mixture was diluted with toluene andthe volatiles were removed by evaporation. The residue was trituratedwith methylene chloride/ether, the solid was collected by filtration anddried under vacuum to give4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazolinehydrochloride (260 mg, 90%).

2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol was prepared as follows:

A solution of di-t-butyldicarbonate (4.52 g, 20 mmol) in THF (10 ml) wasadded to a solution of 2-(N-methylamino)ethanol (1.5 g, 20 mmol) in amixture of water (10 ml) and THF (10 ml). The mixture was stirred atambient temperature for 18 hours, the THF was removed by evaporation andthe aqueous residue was partitioned between ether and water. The organiclayer was washed with water, brine, dried (MgSO₄) and evaporated to give2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (3 g, 85%). ¹H NMR Spectrum(CDCl₃) 1.46(s, 9H); 2.92(s, 3H); 3.39 (t, 2H); 3.75(t, 2H). MS-ES: 176[MH]⁺

EXAMPLE 86

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.62 mmol), (prepared as described for the starting material in Example24), 2-(3,5-dimethyl-[1,2,4)-triazol-4-yl)ethanol (114 mg, 0.81 mmol),(EP 0329357 A1), and triphenylphosphine (492 mg, 1.8 mmol) in methylenechloride (4 ml) and the mixture stirred for 1 hour at ambienttemperature. The precipitated solid was collected by filtration, washedwith ether and dried under vacuum. The solid was dissolved in methylenechloride/methanol and ethereal hydrogen chloride (2 ml of 4.5M solution)was added. The volatiles were removed by evaporation, the residue wassuspended in ether, collected by filtration, washed with ether and driedunder vacuum to give4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl-[1,2,4]-triazol-4-yl)ethoxy)-6-methoxyquinazolinehydrochloride (184 mg, 54%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.78(s,6H); 4.03(s, 3H); 4.57(t, 2H); 4.75(t, 2H); 7.37(s, 1H); 7.46(d, 1H);7.64(t, 1H); 7.66(d, 1H); 8.31(s, 1H); 8.87(s, 1H) MS-ESI: 443 [MH]⁺

Elemental Analysis: Found C 48.0 H 4.6 N 16.1 C₂₁H₂₀N₆O₂ClF 1 H₂ORequires C 47.7 H 4.6 N 15.9% 1.85 HCl

EXAMPLE 87

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to asolution of the 75/25 mixture of 2-(2,4-dimethylimidazol-1-yl)ethanoland 2-(2,5-dimethylimidazol-1-yl)ethanol (114 mg, 0.81 mmol),4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.62 mmol), (prepared as described for the starting material in Example24), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4ml) and the mixture stirred for 4 hours at ambient temperature. Furthertriphenylphosphine (49 mg, 0.18 mmol), mixture of imidazolylethanols (26mg, 0.18 mmol) and diethyl azodicarboxylate (29 μl, 0.18 mmol) wereadded and the mixture stirred for 1 hour. The precipitated solid wascollected by filtration, washed with methylene chloride, and dried undervacuum. The solid was dissolved in methylene chloride/methanol andethereal hydrogen chloride (1.5 ml of a 4.5M solution) was added. Thevolatiles were removed by evaporation, the solid residue was suspendedin ether, collected by filtration, washed with ether and dried undervacuum to give a 75/25 mixture of4-(4-chloro-2-fluoroanilino)-7-(2-(2,4-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride and4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (159 mg, 48%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.23 and2.43(2s, 3H); 2.73 and 2.76(2s, 3H); 4.02(s, 3H); 4.6(br s, 2H); 4.6 and4.75(m, 2H); 7.3-7.5(m, 3H); 7.61(t, 1H); 7.68(d, 1H); 8.24(s, 1H);8.88(s, 1H) MS-ESI: 442 [MH]⁺

Elemental analysis: Found C 49.9 H 4.6 N 13.3 C₂₂H₂₁N₅O₂ClF 1.1 H₂ORequires C 50.1 H 4.8 N 13.3% 1.85 HCl

The starting material was prepared as follows:

2,4-Dimethylimidazole (1.5 g, 15.6 mmol) was added in portions to asuspension of sodium hydride (936 mg of a 60% suspension in mineral oil,23 mmol) in DMF (8 ml) and the mixture was stirred for 30 minutes atambient temperature. 2-Bromoethanol (1.66 ml, 23 mmol) was added and themixture stirred at 100° C. for 16 hours. The solvent was removed byevaporation and concentrated hydrochloric acid (1 ml) was added to theresidue. The resulting solid was triturated with methylene chloride,collected by filtration and dried under vacuum. The solid was purifiedby column chromatography on neutral alumina eluting with methylenechloride/methanol (97/3) and then column chromatography eluting withmethylene chloride/methanol (93/7 followed by 90/10) to give a 75/25mixture of 2-(2,4-dimethylimidazol-1-yl)ethanol and2-(2,5-dimethylimidazol-1-yl)ethanol (650 mg, 29%). MS-ESI: 140 [MH]⁺

EXAMPLE 88

Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (393 mg, 1.5 mmol) and 2-(3-pyridyl)ethanol (86 mg,0.7 mmol), (J.Heterocycl. Chem. 1992, 29, 1663), in methylene chloride(6 ml) and the mixture stirred for 4 hours at ambient temperature. Themixture was poured directly on to a silica column and eluted withmethylene chloride/acetonitrile/methanol (60/35/5). The purified solidwas dissolved in methylene chloride/methanol and ethereal hydrogenchloride (1.5 ml of a 4.5M solution) was added. The volatiles wereremoved by evaporation, the solid residue was suspended in ether,collected by filtration, washed with ether and dried under vacuum togive4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyl)ethoxy)quinazolinehydrochloride (154 mg, 52%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.45(t,2H); 4.01(s, 3H); 4.56(t, 2H); 7.44(s, 1H); 7.46(d, 1H); 7.61(t, 1H);7.67(d, 1H); 8.13(t, 1H); 8.19(s, 1H); 8.71(d, 1H); 8.88(s, 1H); 8.9(d,1H); 9.01(s, 1H) MS-ESI: 425 [MH]⁺

Elemental analysis: Found C 52.7 H 4.3 C₂₂H₁₈N₄O₂ClF 0.8 H₂O 1.8 HClRequires C 52.3 H 4.3%

EXAMPLE 89

Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to asuspension of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5mmol), (prepared as described for the starting material in Example 24),triphenylphosphine (393 mg, 1.5 mmol) and 2-(6-methyl-2-pyridyl)ethanol(96 mg, 0.7 mmol), (J. Chem. Soc. A, 1971, 388), in methylene chloride(6 ml) and the mixture stirred for 16 hours at ambient temperature. Themixture was poured directly on to a silica column and eluted withmethylene chloride/methanol (95/5). The purified solid was dissolved inmethylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a4.5M solution) was added. The mixture was diluted with ether and theresulting precipitate was collected by filtration, washed with ether anddried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(6-methyl-2-pyridyl)ethoxy)quinazolinehydrochloride (97 mg, 34%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.78(s,3H); 3.64(t, 2H); 3.98(s, 3H); 4.67(t, 2H); 7.46(s, 1H); 7.48(br s, 1H);7.62(t, 1H); 7.68(dd, 1H); 7.85(d, 1H); 7.94(d, 1H); 8.19(s, 1H);8.48(t, 1H); 8.88(s, 1H) MS-ESI: 439 [MH]⁺

Elemental Analysis: Found C 52.7 H 4.5 N 10.7 C₂₃H₂₀N₄O₂ClF 1 H₂O 1.8HCl Requires C 52.9 H 4.6 N 10.7%

EXAMPLE 90

A mixture of 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline(49 mg, 0.16 mmol) and 3-hydroxyaniline (21 mg, 0.19 mmol) inisopropanol (3 ml) and isopropanolic hydrogen chloride (0.2 ml of a 5Msolution) was stirred at 80° C. for 1 hour. The precipitated solid wascollected by filtration, washed with isopropanol and ether and driedunder vacuum to give4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (56 mg, 93%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 4.01(s,3H); 4.64(t, 2H); 4.78(t, 2H); 6.71(d, 1H); 7.1(m, 2H); 7.28(t, 1H);7.41(s, 1H); 7.74(s, 1H); 7.83(s, 1H); 8.21(s, 1H); 8.87(s, 1H); 9.22(s,1H) MS-ESI: 378 [MH]⁺

Elemental Analysis: Found C 52.7 H 4.9 N 15.1 C₂₀H₁₉N₅O₃ 0.6 H₂O 1.85HCl Requires C 52.7 H 4.9 N 15.4%

The starting material was prepared as follows:

Diethyl azodicarboxylate (435 mg, 2.5 mmol) was added dropwise to asuspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(612 mg, 2 mmol), (prepared as described for the starting material inExample 85), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J. Med. Chem.1993, 25 4052-4060), and triphenylphosphine (655 mg, 2.5 mmol) inmethylene chloride (10 ml) at 5° C. The mixture was stirred for 10minutes at 5° C. and then 1 hour at ambient temperature. The mixture waspoured directly on to a silica column and eluted with methylenechloride/methanol (95/5) to give7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(640 mg, 80%). ¹H NMR Spectrum: (CDCl₃) 1.19(s, 9H); 3.98(s, 3H);4.34(m, 2H); 4.45(m, 2H); 5.94(s, 2H); 7.02(s, 1H); 7.07(s, 1H); 7.11(s,1H); 7.64(s, 1H); 7.67(s, 1H); 8.17(s, 1H) MS-ESI: 423 [MNa]⁺

Elemental Analysis: Found C 58.3 H 6.4 N 13.9 C₂₀H₂₄N₄O₅ 0.7 H₂ORequires C 58.2 H 6.2 N 13.6%

A solution of7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(640 mg, 1.6 mmol) in saturated methanolic ammonia (10 ml) was stirredfor 15 hours at ambient temperature. The volatiles were removed byevaporation, the solid was triturated with ether, collected byfiltration and dried under vacuum to give7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 90%). ¹H NMR Spectrum: (DMSOd₆) 3.89(s, 3H); 4.4-4.5(m, 4H); 6.9(s,1H); 7.16(s, 1H); 7.28(s, 1H); 7.47(s, 1H); 7.7(s, 1H); 7.99(s, 1H)MS-ESI: 287 [MH]⁺

Elemental Analysis: Found C 57.8 H 5.2 N 19.3 C₁₄H₁₄N₄O₃ 0.3 H₂ORequires C 57.7 H 5.1 N 19.2%

A mixture of7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated atreflux for 1hour. The mixture was diluted with toluene and the volatileswere removed by evaporation. The residue was suspended in methylenechloride, cooled to 0° C. and aqueous sodium hydrogen carbonate solutionwas added. The resulting precipitate was collected by filtration anddried under vacuum to give4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).¹H NMR Spectrum: (DMSOd₆) 4.01(s, 3H); 4.47(m, 2H); 4.53(m, 2H); 6.89(s,1H); 7.27(s, ¹H); 7.41(s, 1H); 7.49(s, 1H); 7.70(s, 1H); 8.88(s, 1H)MS-ESI: 327 [MNa]⁺

EXAMPLE 91

Diethyl azodicarboxylate (220 μl, 1.4 mmol) was added dropwise to asolution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline(150 mg, 0.47 mmol), (prepared as described for the starting material inExample 24), 2-(1,2,4-triazol-4-yl)ethanol (64 mg, 0.56 mmol) andtriphenylphosphine (369 mg, 1.4 mmol) in methylene chloride (5 ml) andthe mixture stirred for 30 minutes at ambient temperature. Further2-(1,2,4-triazol-4-yl)ethanol (16 mg, 0.14 mmol), triphenylphosphine (37mg, 0.14 mmol) and diethyl azodicarboxylate (22 μl, 0.14 mmol) was addedand the mixture stirred for 1 hour at ambient temperature. Theprecipitated solid was collected by filtration, washed with methylenechloride and methanol and dried under vacuum. The solid was dissolved inmethylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a2.2M solution) was added. The volatiles were removed by evaporation, thesolid residue was suspended in ether, collected by filtration, washedwith ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-4-yl)ethoxy)quinazolinehydrochloride (93 mg, 40%). ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 4.02(s,3H); 4.66(t, 2H); 4.85(t, 2H); 7.41(s, 1H); 7.46(dd, 1H); 7.62(t, 1H);7.69(dd, 1H); 8.11(s, 1H); 8.89(s, 1H); 9.55 (s, 2H) MS-ESI: 415 [MH]⁺

Elemental analysis: Found C 45.9 H 3.7 N 17.1 C₁₉H₁₆N₆O₂ClF 0.5 H₂O 2HCl Requires C 45.9 H 3.9 N 16.9%

The starting material was prepared as follows:

A solution of N,N-dimethylformamide azine (1 g, 7 mmol), (J. Chem. Soc.C, 1967, 1664), p-toluene sulphonic acid (45 mg) and ethanolamine (4.3g, 70mmol) in benzene (15 ml) was heated at reflux for 8 hours. Themixture was allowed to cool, the solvent was removed by evaporation andthe residue was purified by column chromatography eluting with methylenechloride/methanol (90/10 followed by 85/15) to give2-(1,2,4-triazol-4-yl)ethanol (328 mg, 41%). ¹H NMR Spectrum: (CDCl₃)3.97(t, 2H); 4.11(t, 2H); 4.9(br s, 1H); 8.06(s, 2H) MS-ESI: 113 [MH]⁺

EXAMPLE 92

1,1′-(azodicarbonyl)dipiperidine (480 mg, 1.9 mmol) was added inportions to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg,0.63 mmol), 3-benzyloxypropanol (150 μl, 0.95 mmol) andtributylphosphine (459 μl, 1.86 mmol) in methylene chloride (20 ml) at5° C. The reaction was stirred for 1 hour at 5° C. and then for 18 hoursat ambient temperature. The mixture was diluted with ether and stirredfor 15 minutes. The insolubles were removed by filtration and thevolatiles were removed from the filtrate by evaporation. The residue waspartitioned between ethyl acetate and water, and the organic layer wasseparated, dried (MgSO₄) and the solvent removed by evaporation. A 1Msolution of ethereal hydrogen chloride was added to the residue, theresulting solution was reduced in volume by evaporation and theresulting precipitate was collected by filtration and dried to give7-(3-benzyloxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolinehydrochloride (90 mg, 31%). ¹H NMR Spectrum (CDCl₃) 2.12(t, 2H); 3.62(t,2H); 4.00(t, 3H); 4.28(t, 2H); 4.45(s, 2H); 7.21-7.38(m, 6H); 7.42(d1H); 7.60(t, 1H); 7.64(dd, 1H); 8.22(s, 1H); 8.80(s, 1H) MS-ESI: 468[MH]⁺

EXAMPLE 93

1,1′-(azodicarbonyl)dipiperidine (840 mg, 3 mmol) was added in portionsto a mixture of4-(⁴-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (315 mg, 1mmol), ethyl 4-hydroxymethyl-2-pyridinecarboxylate (250 mg, 1.4 mmol),(J. Het. Chem. 1993, 30, 631-635) and tributylphosphine (800 μl, 3 mmol)in methylene chloride (50 ml) at 0° C. The mixture was allowed to warmto ambient temperature over 2 hours, the insolubles were removed byfiltration and the filtrate was washed with water and brine, dried(Na₂SO₄) and the solvent removed by evaporation. The residue waspurified by column chromatography eluting with methylenechloride/methanol (10:0 increasing to 9:1). The purified product wasrecrystallised from methylene chloride/hexane to give4-(4-chloro-2-fluoroanilino)-7-(2-ethoxycarbonylpyrid-4-yl)methoxy-6-methoxyquinazoline(285 mg, 60%). m.p. 212-214° C. ¹H NMR Spectrum (DMSOd₆) 1.30(t, 3H);3.96(s, 3H); 4.35(q, 2H); 5.45(s, 2H); 7.14(s, 1H); 7.35(dd, 1H);7.5-7.6(m, 2H); 7.85(s, 1H); 8.15(s, 1H); 8.35(s, 1H); 8.75(d, 1H);9.55(s, 1H)

Elemental analysis: Found C 58.9 H 4.4 N 12.0 C₂₄H₂₀ClFN₄O₄ 0.5 H₂ORequires C 58.7 H 4.4 N 11.5%

EXAMPLE 94

1,1′-(azodicarbonyl)dipiperidine (1.68 g, 6 mmol) was added in portionsto a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2mmol), 4-hydroxymethyl-2-(methylamino)pyridine (385 mg, 2.8 mmol) andtributylphosphine (1.6 ml, 6 mmol) in methylene chloride (50 ml) at 0°C. The mixture was allowed to warm to ambient temperature over 2 hours,the insolubles were removed by filtration and the filtrate was washedwith water and brine, dried (Na₂SO₄) and the solvent removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol (10:0 increasing to 9:1). The purifiedproduct was dissolved in acetone/methanol and a 1M solution of etherealhydrogen chloride was added. The resulting precipitate was collected byfiltration and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-(methylamino)pyrid-4-yl)methoxy-6-methoxyquinazolinehydrochloride (395 mg, 45%). ¹H NMR Spectrum (DMSOd₆) 2.95(d, 3H);4.05(s, 3H); 5.42(s, 2H); 6.90(d, 1H); 7.15(s, 1H); 7.40(d, 1H); 7.44(s,1H); 7.58(t, 1H); 7.62(dd, 1H); 7.95(d, 1H); 8.46(s, 1H); 8.75(s, 1H);9.06(br s, 1H); 11.83(br s, 1H) MS-ESI: 440 [MH]⁺

The starting material was prepared as follows :

A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (preparedas described for the starting material in Example 58), and methylamine(30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16hours at 200° C. The mixture was allowed to cool and the mixturepartitioned between saturated aqueous sodium hydrogen carbonate solutionand ethyl acetate. The organic layer was separated, dried (MgSO₄) andthe volatiles removed by evaporation. The residue was purified by columnchromatography eluting with ethyl acetate to give4-hydroxymethyl-2-(methylamino)pyridine (440 mg, 46%) as a yellow oil.¹H NMR Spectrum (DMSOd₆) 2.72(d, 3H); 4.35(d, 2H); 5.15(t, 1H); 6.30(brd, 1H); 6.35(d, 1H); 6.38(s, 1H); 7.85(d, 1H)

EXAMPLE 95

1,1′-(azodicarbonyl)dipiperidine (1.68 g, 6 mmol) was added in portionsto a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2mmol), 4-hydroxymethyl-2-(dimethylamino)pyridine (426 mg, 2.8 mmol) andtributylphosphine (1.6 ml, 6 mmol) in methylene chloride (50 ml) at 0°C. The mixture was allowed to warm to ambient temperature over 2 hours,the insolubles were removed by filtration and the filtrate was washedwith water and brine, dried (Na₂SO₄) and the solvent removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol (100:0 increasing to 95:5). Thepurified product was dissolved in acetone/methanol and a 1M solution ofethereal hydrogen chloride was added. The resulting precipitate wascollected by filtration and dried to give4-(4-chloro-2-fluoroanilino)-7-(2-(dimethylamino)pyrid-4-yl)methoxy-6-methoxyquinazolinehydrochloride (305 mg, 30%). m.p. 290° C. ¹H NMR Spectrum (DMSOd₆)3.05(s, 6H); 4.05(s, 3H); 5.45(s, 2H); 6.95(d, 1H); 7.35(s, 1H);7.42(dd, 1H); 7.56(t, 2H); 7.62(dd, 1H); 8.00(d, 1H); 8.55(s, 1H),9.80(s, 1H); 11.95(br s, 1H) MS-ESI: 454 [MH]⁺

Elemental analysis: Found C 47.2 H 4.9 N 12.1 C₂₃H₂₁ClFN₅O₂ 3 HCl H₂ORequires C 47.6 H 4.5 N 12.1%

The starting material was prepared as follows:

A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (preparedas described for the starting material in Example 58), and dimethylamine(30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16hours at 200° C. The mixture was allowed to cool and the mixturepartitioned between saturated aqueous sodium bicarbonate solution andethyl acetate. The organic layer was separated, dried (MgSO₄) and thevolatiles removed by evaporation. The residue was purified by columnchromatography eluting with ethyl acetate to give4-hydroxymethyl-2-(dimethylamino)pyridine (1 g, 94%) as a yellow oil. ¹HNMR Spectrum (DMSOd₆) 3.00(s, 6H); 4.40(d, 2H); 5.20(t, 1H); 6.45(d,1H); 6.55(s, 1H); 7.96(d, 1H) MS-ESI: 153 [MH]⁺

EXAMPLE 96

A mixture of 4-(3-hydroxyprop-2-en-1-yl)pyridine (180 mg, 1.3 mmol) andthionyl chloride (0.3 ml) in toluene (10 ml) was stirred at roomtemperature for 2 hours. The volatiles were removed by evaporation togive crude 4-(3-chloroprop-2-en-1-yl)pyridine hydrochloride (180 mg,0.94 mmol)) This product was added to a mixture of4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (500 mg, 1.6mmol) and potassium carbonate (500 mg, 4.9 mmol) in DMF (20 ml) and themixture stirred at 100° C. for 1 hour. The reaction mixture was allowedto cool and partitioned between ethyl acetate and water. The organiclayer was separated, washed with water and brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (100/0increasing to 95/5) and then by reverse phase (C18) HPLC eluting withmethanol/water (30/70 increasing to 50/50) to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(pyrid-4-yl)prop-2-en-1-yloxy)quinazoline(1.5 mg, 4%). ¹H NMR Spectrum (DMSOd₆) 4.00(s, 3H); 5.05(d, 2H); 6.93(d,1H); 7.11(dt, 1H); 7.40(s, 1H); 7.40-7.43(m, 2H); 7.60(t, 1H); 7.65(d,1H); 7.80(m, 2H); 8.05(s, 1H); 8.70(br s, 2H) MS-ESI: 437 [MH]⁺

The starting material was prepared as follows:

n-Butyllithium (25 ml of a 1.6M solution in hexane, 40 mmol) was addeddropwise to a stirred suspension of 2-hydroxyethyltriphenylphosphoniumbromide (7.74 g, 20 mmol) in THF (50 ml) at −70° C. and the mixtureallowed to warm to −30° C. and stirred for 2 hours.4-Pyridinecarboxaldehyde (2.16 g, 20 mmol) was added to the resultingred solution, and the mixture stirred for 1 hour at −30° C. and thencooled to −70° C. n-Butyllithium (12.5 ml of a 1.6M solution in hexane,20 mmol) was added and the reaction mixture stirred at −70° C. for 1hour. The mixture was quenched with isopropanol and allowed to warm toambient temperature. Saturated aqueous ammonium chloride solution wasadded, the organic layer separated and the aqueous layer extracted withethyl acetate (3×50 ml). The combined extracts were washed with brineand dried (MgSO4) and the volatiles removed by evaporation. The residuewas purified by column chromatography eluting with ethyl acetate to give4-(3-hydroxyprop-2-en-1-yl)pyridine MS-ESI: 136 [MH]⁺

EXAMPLE 97

suspension of4-chloro-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline (214 mg,0.7 mmol), 4-bromo-2-fluoroaniline (160 mg, 0.84 mmol) in isopropanolichydrogen chloride (1 ml of a 5M solution) and isopropanol (5 ml) washeated at 80° C. for 1 hour. The mixture was allowed to cool, theprecipitate was collected by filtration, washed with isopropanol andthen ether and dried under vacuum at 70° C. to give4-(4-bromo-2-fluoroanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride (55 mg, 15%). ¹H NMR Spectrum (DMSOd₆) 3.99(s, 3H);4.62(t, 2H); 4.75(t, 2H); 7.37(s, 1H); 7.5-7.7(m, 2H); 7.81(d, 1H);8.04(s, 1H); 8.24(s, 1H); 8.63(s, 1H); 8.84(s, 1H); 11.52(s, 1H) MS-ESI:459 [MH]⁺

Elemental analysis Found C 41.8 H 3.4 N 15.6 C₁₉H₁₆BrFN₆O₂ 0.8 H₂ORequires C 42.0 H 3.6 N 15.5% 1.9 HCl

The starting material was prepared as follows:

Diethyl azodicarboxylate (1.1 ml, 7 mmol) was added dropwise to asolution of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one-(1.7g, 5.55 mmol), 2-(1,2,4-triazol-1-yl)ethanol (791 mg, 7 mmol), (Ann.Pharm. Fr. 1977,35,503-508) and triphenylphosphine (1.8 g, 7 mmol)cooled at 5° C. The mixture was allowed to warm to ambient temperatureand stirred for 1 hour. The mixture was poured directly on to a columnof silica and eluted with methylene chloride/methanol (95/5) to give6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one(1.64 g, 74%). ¹H NMR Spectrum (DMSOd₆, CF₃COOD) 1.12(s, 9H); 3.87(s,3H) 4.57(t, 2H); 4.74(t, 2H); 5.92(s, 2H); 7.24(s, 1H); 7.51(s, 1H);8.36(d, 1H); 8.41(s, 1H); 9.02(d, 1H) MS-ESI: 424 [MNa]⁺

Elemental analysis Found C 56.5 H 6.0 N 17.6 C₁₉H₂₃N₅O₅ Requires C 56.9H 5.8 N 17.%

A solution of6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one(1.6 g, 4 mmol) in saturated methanolic ammonia (25 ml) was stirred atambient temperature for 2 days. The volatiles were removed byevaporation, the solid residue was triturated with ether, collected byfiltration and dried under vacuum to give6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one(1.11 g, 98%) ¹H NMR Spectrum (DMSO d₆) 3.84(s, 3H); 4.51(t, 2H);4.65(t, 2H); 7.16(s, 1H); 7.44(s, 1H); 7.89(s, 1H); 7.99(s, 1H); 8.55(s,1H) MS-El: 287 [M]⁺

Elemental analysis Found C 53.9 H 4.6 N 24.6 C₁₃H₁₃N₅O₃ Requires C 54.4H 4.6 N 24.4

A solution of6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one(1.11 g, 3.86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) washeated at reflux for 1 hour. The mixture was allowed to cool, toluenewas added and the volatiles were removed by evaporation. The residue waspartitioned between methylene chloride and water and the aqueous layerwas adjusted to pH8.5 with saturated aqueous sodium hydrogen carbonatesolution. The organic layer was separated, washed with brine, dried(MgSO₄), and the solvent removed by evaporation. The residue waspurified by column chromatography eluting with methylenechloride/methanol (95/5). The purified solid was triturated with ether,collected by filtration, washed with water and then ether, and driedunder vacuum to give4-chloro-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline (756 mg,65%). ¹H NMR Spectrum (DMSO d₆) 3.97(s, 3H); 4.65(dd, 2H); 4.70(dd, 2H);7.39(s, 1H); 7.52(s, 1H); 7.99(s, 1H); 8.57(s, 1H); 8.89(s, 1H) MS-ESI:306 [MH]⁺

EXAMPLE 98

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium  12.0 Maize starch paste (5% w/v paste)  2.25Magnesium stearate  3.0 (b) Tablet II Compound X  50 Lactose Ph.Eur223.75 Croscarmellose sodium  6.0 Maize starch  15.0Polyvinylpyrrolidone (5% w/v paste)  2.25 Magnesium stearate  3.0 (c)Tablet III Compound X  1.0 Lactose Ph.Eur  93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste)  0.75 Magnesium stearate  1.0 (d)Capsule mg/capsule Compound X  10 Lactose Ph.Eur 488.5 Magnesiumstearate  1.5 (e) Injection I (50 mg/ml) Compound X  5.0% w/v 1N Sodiumhydroxide solution  15.0% v/v 0.1 N Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400  4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X  1.0% w/v Sodium phosphate BP  3.6%w/v 0.1 N Sodium hydroxide solution  15.0% v/v Water for injection to100% (g) Injection III (1 mg/ml, buffered to pH6) Compound X  0.1 % w/vSodium phosphate BP  2.26% w/v Citric acid  0.38% w/v Polyethyleneglycol 400  3.5% w/v Water for injection to 100% Note The aboveformulations may be obtained by conventional procedures well known inthe # pharmaceutical art. The tablets (a)-(c) may be enteric coated byconventional means, for example # to provide a coating of celluloseacetate phthalate.

What is claimed is:
 1. A quinazoline derivative of the formula Ia:

wherein: Y¹ represents —O—, —NH—, —S— or —CH₂—; n is an integer from 0to 5; X¹ represents a phenyl group or a 5- or 6-membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl or heterocyclic group may carry up to 5 substituentsselected from halogeno, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴¹R⁴² and —NR⁴³COR⁴⁴, whereinR⁴¹, R⁴², R⁴³ and R⁴⁴, which may be the same or different, eachrepresents hydrogen or C₁₋₄alkyl; R¹ represents hydrogen, hydroxy,C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, or NR⁴⁵R⁴⁶, wherein R⁴⁵ and R⁴⁶,which may be the same or different, each represents hydrogen orC₁₋₃alkyl; R² represents hydrogen, hydroxy, halogeno, C₁₋₃alkyl,C₁₋₃alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from1 to 5; R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino or nitro; Z represents—NH—; and Y⁶ represents a direct bond; and salts thereof.